Benzene fused heterocyclic derivatives having thromboxane A2 receptor antagonistic activity and prostaglandin I2 Agonistic activity and application thereof

ABSTRACT

Benzene fused derivatives represented by the following formula:having strong TXA2 receptor antagonistic action and PGI2 receptor agonistic action, and effective for treating or preventing diseases concerning TXA2.

TECHNICAL FIELD

The present invention relates to novel benzene fused ring derivatives,and a thromboxane A₂ (referred to as “TXA₂” hereinafter) receptorantagonist comprising one of the compounds as an active component.

BACKGROUND ART

TXA₂ discovered by Samuelsson et al in 1975 has strong plateletaggregating action, vascular smooth muscle contracting action andbronchial smooth muscle contracting action (Proc. Natl. Acad. Sci.U.S.A., 72, 2994 (1975)). On the other hand, as a compound havingreverse actions, i.e., strong platelet aggregation inhibiting action andvascular relaxing action, prostaglandin I₂ (PGI₂) is known (Nature, 263,663 (1976)). Both compounds are synthesized from arachidonic acid invivo, and it is said that a balance between TXA₂ and PGI₂ greatlyconcerns maintenance of the homeostasis of the circulatory systembecause of the strong actions thereof. Therefore, with the balanceshifted to the TXA₂ side, phenomena such as activation of the plateletsand subsequent thrombogenesis and vascular contraction occur. This ispossibly a factor that causes ischemic heart diseases such as anginapectoris, myocardial infarction, etc., and circulatory diseases such ascelebrovascular disorder, nephropathy, etc. It is also thought that TXA₂concerns bronchial asthma because of its strong bronchial smooth musclecontracting action. Therefore, in order to treat ischemic heart diseasessuch as angina pectoris, myocardial infarction, etc., circulatorydiseases such as celebrovascular disorder, nephropathy, etc., orbronchial asthma or the like, it is thought to be important to returnthe off-balance state of TXA₂ and PGI₂ to the normal state, and amedicine for inhibiting the action of TXA₂ or a medicine having theaction as a PGI₂ receptor agonist is thought to be effective to treatthese diseases. As medicines for inhibiting the actions of TXA₂concerning the occurrence of the above-described diseases, TXA₂ receptorantagonists have been reported so far (Circulation, 81, Suppl I, I-69(1990), Medicinal Research Reviews, 11, 503 (1991)). However,conventional TXA₂ receptor antagonists exhibit unsatisfactory clinicaleffects.

An object of the present invention is to provide an excellent TXA₂receptor antagonist having the action as a PGI₂ receptor agonist.

DISCLOSURE OF INVENTION

The present invention provides benzene fused heterocyclic derivativesrepresented by the following formula (I):

wherein

A¹ is —CH₂—, —O—, —S—, or —NR⁴—, wherein R⁴ is hydrogen or alkyl having1 to 5 carbon atoms;

A² is —(N—)—CH₂, —(N—)—CO—, —(CH—)—, or —(C—)═CH—;

A³ is alkylene having 1 to 4 carbon atoms, alkenylene having 2 to 4carbon atoms, or alkynylene having 2 to 4 carbon atoms;

A⁴ is —S(O)_(p)—, —O—, —CH₂—, —NR⁵—, —NR⁵CO—, or —CONR⁵—, wherein R⁵ ishydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may besubstituted by a group or groups selected from alkyl having 1 to 5carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms,phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylaminohaving 1 to 5 carbon atoms), and p is an integer of 0 to 2;

m is an integer of 1 to 3;

R¹ is —X—(CH₂)_(n)COOR⁶ wherein X is —O—, —S—, or —CH₂—, R⁶ is hydrogen,alkyl having 1 to 5 carbon atoms, or an atom or group which gives apharmacologically acceptable salt, and n is an integer of 1 to 3;

R² is the following:

(1) —Ar (wherein Ar is phenyl, naphthyl, furyl, or thienyl (whereinphenyl, naphthyl, furyl, or thienyl may be substituted by a group orgroups selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl,alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl,cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms); or

(2) alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbonatoms, or alkynyl having 2 to 5 carbon atoms, wherein alkyl, alkenyl, oralkynyl is substituted by one or two Ar (wherein Ar is defined as thesame as the above), and may be further substituted by a group or groupsselected from —OH, —CF₃, and cycloallyl having 3 to 8 carbon atoms);

R³ is hydrogen, halogen, alkyl having 1 to 5 carbon atoms, or alkoxyhaving 1 to 5 carbon atoms: and

either or both of A¹ and A² contain a hetero atom other than carbon. Thepresent invention also provides a TXA₂ receptor antagonist containingone of the above compounds of the present invention as an activeingredient.

The compounds of the present invention have strong TXA₂ receptorantagonistic action and PGI₂ receptor agonistic action, and areeffective as medicines for treating or preventing diseases concerningTXA₂.

BEST MODE FOR CARRYING OUT THE INVENTION

Of the compounds represented by the above formula (I), compoundsrepresented by the following formula (II) are preferred.

[wherein R¹, R², R³, A₁, A², A³, A⁴ and m are defined as the same as theabove].

Although R¹, R², R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, m, n, and Ar informula (I) or (II) are defined as described above, these groups aredescribed in further detail below.

R¹ is —X—(CH₂)_(n)—COOR⁶ (wherein X is —O—, —S—, or —CH₂—, R⁶ ishydrogen, alkyl having 1 to 5 carbon atoms, or an atom or group whichgives a pharmacologically acceptable salt, and n is an integer of 1 to3). X is particularly preferably —O—, and n is preferably 1 or 2, morepreferably 1.

Examples of alkyl R⁶ having 1 to 5 carbon atoms include methyl, ethyl,propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl,1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like.

Examples of pharmacologically acceptable cations of R⁶ include metalcations, ammonium, amine cations, and quaternary ammonium cations.Preferred examples of metal cations include cations derived from alkalimetals, for example, such as lithium, sodium, and potassium, alkaliearth metals, for example, such as magnesium and calcium. Of course, thepresent invention include cations of other metals, for example, such asaluminum, zinc, and iron.

Pharmacologically acceptable amine cations are derived from primary,secondary or tertiary amines. Examples of suitable amines includemethylamine, dimethylamine, triethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, similar aliphatic, alicyclic orheterocyclic amines having up to 18 carbon atoms, for example, such as1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrolidine,2-methylpyrolidine, 4-dimethylpiperazine, 2-methylpiperidine, and thelike, amines containing water-soluble or hydrophilic groups, forexample, such as mono-, di-, or tri-ethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,tris(hydroxymethyl)aminomethane, N-phenylethanolamine,N-(p-aminophenyl)diethanolamine, galactamine, N-methylglucamine,N-methylglucosamine, ephedrine, phenylephedrine, epinephrine, procaine,and the like, basic amino acids such as lysine, alginine, and the like.

R² is preferably alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5carbon atoms, or alkynyl having 2 to 5 carbon atoms (alkyl, alkenyl, oralkynyl is substituted by an one or two Ar (Ar is phenyl, naphthyl,furyl, or thienyl (phenyl, naphthyl, furyl, or thienyl may besubstituted by a group selected from alkyl having 1 to 5 carbon atoms,phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen,trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5carbon atoms)), and may be further substituted by a group selected from—OH, —CF₃, and cycloalkyl having 3 to 8 carbon atoms), more preferablyalkyl having 1 to 5 carbon atoms, which is substituted by one or two Ar(Ar is defined as the same as the above). Particularly, alkyl having 1to 5 carbon atoms, which is substituted by one or two phenyl groups(which may be substituted by a group selected from alkyl having 1 to 5carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms,phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylaminohaving 1 to 5 carbon atoms) is preferred, and alkyl having 1 to 5 carbonatoms, which is substituted by two phenyl groups (which may besubstituted by a group selected from alkyl having 1 to 5 carbon atoms,phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen,trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5carbon atoms) is more preferred.

Where R² is alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5carbon atoms, or alkynyl having 2 to 5 carbon atoms, which issubstituted by two Ar, the two Ar groups may be the same or different.

Of Ar groups, thienyl is 2-thienyl or 3-thienyl, furyl is 2-furyl or3-furyl, and naphthyl is 1-naphthyl or 2-naphthyl.

Examples of alkyl R² having 1 to 5 carbon atoms which is substituted byone or two Ar include benzyl, phenethyl, phenylpropyl, phenylbutyl,phenylpentyl, diphenylmethyl, 1,1-diphenylethyl, 2,2-diphenylethyl,1,3-diphenylpropyl, 3,3-diphenylpropyl, 3,3-diphenyl-2-methylpropyl,3,3-diphenylbutyl, 1,4-diphenylbutyl, 2,4-diphenylbutyl,3,4-diphenylbutyl, 4,4-diphenylbutyl, 4,4-diphenyl-2-methylbutyl,4,4-diphenyl-3-methylbutyl, 4,4-diphenylpentyl, 1,5-diphenylpentyl,4,5-diphenylpentyl, 5,5-diphenylpentyl, 2-thienylmethyl,3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 1-naphthylmethyl,2-naphthylmethyl, phenyl(2-thienyl)methyl, phenyl(2-furyl)methyl,bis(2-thienyl)methyl, bis(2-furyl)methyl, and the like.

Examples of alkenyl R² having 2 to 5 carbon atoms which is substitutedby one or two Ar include 2-phenylvinyl, 3-phenyl-2-propenyl,2-phenyl-1-methylvinyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl,2,2-diphenylvinyl, 3,3-diphenyl-2-propenyl, 3,3-diphenyl-1-propenyl,4,4-diphenyl-3-butenyl, 1,4-diphenyl-3-butenyl, 2,4-diphenyl-3-butenyl,3,4-diphenyl-2-butenyl, 4,4-diphenyl-2-butenyl,4,4-diphenyl-2-methyl-3-butenyl, 4,4-diphenyl-3-methyl-3-butenyl,5,5-diphenyl-4-pentenyl, 1,5-diphenyl-4-pentenyl,4,5-diphenyl-3-pentenyl, 4,4-diphenyl-2-pentenyl,3,3-bis(2-thienyl)-2-propynyl, 3,3-bis(2-furyl)-2-propynyl,3,3-bis(1-naphthyl)-2-propynyl, and the like.

Examples of alkynyl R² having 1 to 5 carbon atoms which is substitutedby one or two Ar include 3-phenyl-2-propynyl, 4-phenyl-2-butynyl,5-phenyl-3-pentynyl, 3,3-diphenyl-1-propynyl, 3,3-diphenyl-1-butynyl,4,4-diphenyl-2-butynyl, 5,5-diphenyl-3-pentynyl,4,4-bis(2-thienyl)-2-butynyl, 4,4-bis(2-furyl)-2-butynyl,4,4-bis(1-naphthyl)-2-butynyl, and the like.

A phenyl group, a naphthyl group, a furyl group, or a thienyl grouprepresented by Ar may be substituted by a group selected from alkylhaving 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino,and alkylamino having 1 to 5 carbon atoms. Preferred examples of alkylhaving 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Preferredexamples of alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy,propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy,t-butyloxy, pentyloxy, and the like. Preferred examples of halogeninclude fluorine, chlorine, bromine, and iodine. Preferred examples ofalkylamino having 1 to 5 carbon atoms include methylamino,dimethylamino, ethylamino, diethylamino, diisopropylamino,di-t-butylamino, and the like.

Examples of alkyl R³ having 1 to 5 carbon atoms include methyl, ethyl,propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl,1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like. Examplesof alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy,pentyloxy, and the like. Examples of halogen include fluorine, chlorine,bromine, and iodine.

A¹ is —CH₂—, —O—, —S—, or —NR⁴— (wherein R⁴ is hydrogen or alkyl having1 to 5 carbon atoms). Examples of alkyl R⁴ having 1 to 5 carbon atomsinclude methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl,t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, andthe like. A¹is more preferably —CH₂— or —O—.

Examples of A² include —(N—)—CH₂—, —(N—)—CO—, —(CH—)—, and —(CH—)═CH—which are respectively represented by the following:

A² is more preferably —(N—)—CH₂— or —(CH—)—.

Examples of alkylene A³ having 1 to 4 carbon atoms include methylene,ethylene, trimethylene, tetramethylene, and the like. Examples ofalkenylene A³ having 2 to 4 carbon atoms include vinylene, propenylene,butenylene, and the like. Examples of alkynylene A³ having 2 to 4 carbonatoms include ethynylene, propynylene, butynylene, and the like.Particularly, alkylene having 1 to 4 carbon atoms such as methylene,ethylene, trimethylene, tetramethylene or the like is preferred.

A⁴ is —S(O)_(p)—, —O—, —CH₂—, —NR⁵—, —NR⁵CO—, or —CONR⁵— (wherein R⁵ ishydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may besubstituted by a group selected from alkyl having 1 to 5 carbon atoms,phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen,trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5carbon atoms), and p is an integer of 0 to 2). Examples of alkyl R⁵having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl,isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, and the like.

Of substituents of a phenyl group R⁵ ₁ preferred examples of alkylhaving 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Preferredexamples of alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy,propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy,t-butyloxy, pentyloxy, and the like. Preferred examples of halogeninclude fluorine, chlorine, bromine, and iodine. Preferred examples ofalkylamino having 1 to 5 carbon atoms include methylamino,dimethylamino, ethylamino, diethylamino, diisopropylamino,di-t-butylamino, and the like.

A¹ is preferably —S(O)_(p)— (p represents an integer of 0 to 2) or —O—,more preferably —S(O)_(p)— (p represents an integer of 0 to 2).

m is an integer of 1 to 3, preferably 1 or 2, more preferably 1.

Although some compounds represented by the above formula (I) haveasymmetric carbon and geometric isomers, the formula (I) of the presentinvention includes all possible stereo isomers and geometric isomers.

Although some examples of the compounds of the present invention arelisted below, the present invention is not limited to these examples.

(1-(4,4-diphenylbutyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid

(1-(4,4-diphenylpentyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid

(1-(2-(diphenylmethoxy)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(1,1-diphenylethoxy)ethyl)-1,2,3,4-tetrahydroquinolin-⁵-yloxy)aceticacid

(1-(2-(benzylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid

(1-(2-(1-phenyl-1-methylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(3-(diphenylmethylthio)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(3-(1,1-diphenylethylthio)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(2,2-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(2,2-diphenylpropylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(2,2,2-trifluoro-1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(diphenylmethylsulfinyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(1,1-diphenylethylsulfinyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(diphenylmethylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(1,1-diphenylethylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(3-diphenylamino-3-oxopropyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(4-diphenylamino-3-oxobutyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-((diphenylmethyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-((1,1-diphenylethyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(2-(diphenylamino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(3-(diphenylamino)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(1-(4-(diphenylamino)butyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

3-(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)propionicacid

4-(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)butyricacid

3-(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)propionicacid

4-(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)butyricacid

(1-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)aceticacid

(1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)aceticacid

(2-oxo-1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(2-oxo-1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

(2-oxo-1-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)aceticacid

(2-oxo-1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)aceticacid

(4-(4,4-diphenylbutyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid

(4-(4,4-diphenylpentyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(benzylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1-phenyl-1-methylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(3-(diphenylmethylthio)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(3-(1,1-diphenylethylthio)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(2,2-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(2,2-diphenylpropylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(2,2,2,-trifluoro-l,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(diphenylmethylsulfinyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethylsulfinyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(diphenylmethylsulfonyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethylsulfonyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(3-diphenylamino-3-oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(4-diphenylamino-3-oxobutyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-((diphenylmethyl)amino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-((1,1-diphenylethyl)amino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(diphenylamino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(3-(diphenylamino)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(4-(diphenylamino)butyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

3-(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)propionicacid

4-(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)butyricacid

3-(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)propionicacid

4-(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)butyricacid

(5-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-9-yloxy)aceticacid

(5-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzoxazepin-9-yloxy)aceticacid

(3-oxo-4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(3-oxo-4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-oxo-5-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-9-yloxy)aceticacid

(4-oxo-5-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzoxazepin-9-yloxy)aceticacid

(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzothiazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzothiazin-8-yloxy)aceticacid

(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydro-1,4-diazin-5-yloxy)aceticacid

(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydro-1,4-diazin-8-yloxy)aceticacid

(3-(4,4-diphenylbutyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

(3-(4,4-diphenylpentyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

(3-(2-(diphenylmethoxy)ethyl)-2,3-dihydrobenzofuran-7-yloxy) acetic acid

(3-(2-(1,1-diphenylethoxy)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(benzylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

(3-(2-(1-diphenyl-1-methylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(3-(diphenylmethylthio)propyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(3-(1,1-diphenylethylthio)propyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(2,2-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(2,2-diphenylpropylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(2,2,2-trifluoro-1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(diphenylmethylsulfinyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(1,1-diphenylethylsulfinyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(diphenylmethylsulfonyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(1,1-diphenylethylsulfonyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(3-diphenylamino-3-oxopropyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(4-diphenylamino-3-oxobutyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-((diphenylmethyl)amino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-((1,1-diphenylethyl)amino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

(3-(2-(diphenylamino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

(3-(3-(diphenylamino)propyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

(3-(4-(diphenylamino)butyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid

3-(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)propionicacid

4-(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)butyricacid

3-(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)propionicacid

4-(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)butyricacid

(4-(2-(diphenylmethylthio)ethyl)-chroman-8-yloxy)acetic acid

(4-(2-(1,1-diphenylethylthio)ethyl)-chroman-8-yloxy)acetic acid

(4-(2-(diphenylmethylthio)ethyl)-2H-chromen-8-yloxy)acetic acid

(4-(2-(1,1-diphenylethylthio)ethyl)-2H-chromen-8-yloxy)acetic acid

The present invention includes methyl esters, ethyl esters, propylesters, isopropyl esters, butyl esters, t-butyl esters, pentyl esters,and the like of the above compounds.

Although examples of methods of producing the compounds included in thepresent invention will be described below, the present invention is notlimited to these examples.

Of the compounds of the present invention, compounds in which A⁴ is —S—and X is —O— can be synthesized by production method A.

(wherein A¹, A², A³, R², R³, and m are defined as the same as the above,R¹¹ represents alkyl having 1 to 5 carbon atoms, R¹² representsp-toluenesulfonyloxy, methanesulfonyloxy, chlorine, bromine, or iodine,R¹³ represents a metal cation such as lithium, sodium, potassium, or thelike, or an amine cation such as an ammonium ion, a monoethanolammoniumion, a diethanolammonium ion, triethanolammonium ion, aN-methylgulcamium ion, an ephedrium ion, or the like, and n representsan integer of 1 to 3).

Step A-1 is the step of introducing an ester unit. This step is carriedout by removing a proton of a phenolic hydroxyl group by using a base,and then reacting the product with the following compound:

Br(CH₂)_(n)COOR¹¹

or

Cl(CH₂)_(n)COOR¹¹

(wherein R¹¹ and n are defined as the same as the above). As the base,potassium carbonate, potassium t-butoxide, potassium hydroxide, sodiumhydroxide, sodium hydride, or the like is used. As a solvent, methanol,ethanol, DMF, DMSO, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step A-2 is the step of converting a hydroxyl group into a leaving groupsuch as p-toluenesulfonyloxy, methanesulfonyloxy, bromine, or the like.Where R¹² is p-toluenesulfonyloxy or methanesulfonyloxy, the conversioncan be performed by conventional tosylation or mesylation. Namely, thestep can be carried out by reaction with p-toluenesulfonyl chloride ormethanesulfonyl chloride in coexistence with a base such astriethylamine, diisopropylamine, pyridine, or the like. As a solvent,THF, DME, dioxane, benzene, toluene, dichloromethane, DMF, or the likeis preferably used, and a base such as pyridine or the like may be usedas the solvent. The reaction temperature is selected from −80 to 150°C., and is preferably −20 to 50° C. The reaction time is 1 minute to 80hours, and is usually 5 minutes to 30 hours. Where R¹² is bromine, theconversion is carried out by reaction with a brominating agent such astriphenylphosphine+carbon tetrabromide,triphenylphosphine+N-bromosuccimide, or the like. As a solvent, THF,DME, dichloromethane, or the like is used. The reaction temperature isselected from −80 to 150° C., and is preferably −20 to 50° C. Thereaction time is 1 minute to 80 hours, and is usually 5 minutes to 30hours.

Step A-3 is the step of thioetherifying compound 3. This step is carriedout by reacting compound 3 with a sodium or potassium salt of R²—SH (R²is defined as the same as the above) which has previously been prepared.A sodium or potassium salt of R²—SH can be obtained by reacting R²—SHwith a base such as sodium hydride, sodium carbonate, sodium t-butoxide,potassium hydride, potassium carbonate, potassium t-butoxide, or thelike. As a solvent, THF, DME, DMF, or the like is used. The reactiontemperature is selected from −80 to 150° C., and is preferably −20 to50° C. The reaction time is 1 minute to 80 hours, and is usually 5minutes to 30 hours. The step can also be carried out by adding a basesuch as potassium carbonate or the like to a solution mixture containingcompound 3 and R²—SH.

Step A-4 is the step of ester hydrolysis of compound 4. Hydrolysisreaction is carried out by reacting ester 4 with a base in a solventsuch as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, orthe like. As the base, a base such as sodium hydroxide, potassiumhydroxide, potassium carbonate, or the like is preferably used. Thereaction temperature is selected from −20 to 150° C., but a preferredreaction rate can be obtained at 0 to 50° C. The reaction time is 1minute to 120 hours, and is usually 5 minutes to 50 hours. Thehydrolysis reaction can also be carried out by reacting compound 4 witha metal salt of a thiol in DMF or DMSO.

Step A-5 is the step of forming a salt of compound 5. Reaction formingsalt is carried out by reacting carboxylic acid 5 with a hydroxide of ametal cation or an amine. As a solvent, water, methanol, ethanol,tetrahydrofuran, ethyl acetate, or the like can be used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 80°C. The reaction time is 1 minute to 120 hours, and is usually 1 minuteto 30 hours.

Of the compounds of the present invention, compounds in which A⁴ is—S(O)_(p)— wherein p is 1, and X is —O— can be synthesized by productionmethod B.

(wherein A¹ A², A³, R², R³, m, n, and R¹³ are defined as the same as theabove).

Of Step B-1 is the step of oxidizing compound 5. Oxidation step iscarried out by reacting sulfide 5 with an oxidizing agent. As theoxidizing agent, m-chloroperbenzoic acid, perbenzoic acid, peraceticacid, hydrogen peroxide solution, or the like is preferably used. As asolvent, carbon tetrachloride, chloroform, dichloromethane, water,acetic acid, methanol, ethanol, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 100°C. The reaction time is 1 minute to 120 hours, and is usually 1 minuteto 30 hours.

Step B-2 is the step of forming a salt of compound 7. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(N—)—CH₂—, A³ is straight chain alkyl having 2 to 4 carbon atoms,A⁴ is —S—, and X is —O— can be produced by production method C.

Step C-1 is the step of nitrating compound 9. Nitration reaction iscarried out by reacting phenol 9 with a nitrating agent. As thenitrating agent, nitric acid, acetic anhydride-nitric acid mixture, anitric acid-sulfuric acid mixture, a trifluoroacetic anhydride -nitricacid mixture, potassium nitrate-trifluoroacetic acid, fuming nitricacid, or the like is preferably used. As a solvent, ethyl acetate,nitromethane, dimethoxyethane, acetic acid, trifluoroacetic acid,methanol, ethanol, water, or the like is used. The reaction temperatureis selected from −50 to 150° C., and is preferably −10 to 50° C. Thereaction time is 1 minute to 120 hours, and is usually 1 minute to 30hours.

Step C-2 is the step of introducing an ester unit in compound 10. Thisstep is carried out by removing a proton of a phenolic hydroxyl group byusing a base, and then reacting the product with the following compound:

Br(CH₂)_(m)COOR¹⁴

or

Cl(CH₂)_(m)COOR¹⁴

(wherein R¹⁴ and m are defined as the same as the above). As the base,potassium carbonate, potassium t-butoxide, potassium hydroxide, sodiumhydroxide, sodium hydride, or the like is used. As a solvent, methanol,ethanol, DMF, DMSO, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably to 50° C.The reaction time is 1 minute to 120 hours, and usually 5 minutes to 50hours.

(wherein R², R³, m, n, R¹¹, R¹², and R¹³ are defined as the same as theabove, R¹⁴ represents alkyl having 1 to 5 carbon atoms, R¹⁵ representsalkyl having 1 to 5 carbon atoms, and q represents an integer of 1 to3).

Step C-3 is the step of reducing and cyclizing compound 11. This step iscarried out by the method of catalytically hydrogenating nitro compound11 or the method of reducing it with a metal reducing agent. Thecatalytic hydrogenation preferably uses hydrogen gas, formic acid,ammonium formate, sodium formate, or the like as a hydrogen source, andpalladium carbon, platinum, platinum oxide, platinum carbon, palladiumacetate, a tetrakistriphenylphosphine palladium complex, or the like asa catalyst. As a reaction additive, hydrochloric acid, sulfuric acid,ammonium chloride, activated carbon, iron powder, zinc powder, or thelike may be used. The reduction method using the metal reducing agentpreferably uses iron, zinc, tin, or the like as the reducing agent. As asolvent, ethyl acetate, acetic acid, trifluoroacetic acid, methanol,ethanol, water, tetrahydrofuran, dimethoxyethane, or the like ispreferably used. As a reaction additive, hydrochloric acid, sulfuricacid, ammonium chloride, activated carbon, an iron powder, a zincpowder, or the like may be further used. The reaction temperature isselected from −50 to 150° C., and is preferably 0 to 120° C. Thereaction time is 1 minute to 120 hours, and is usually 1 minute to 30hours. Where R³ is bromine, in some cases, the use of the catalytichydrogenation method as the reduction method occurs conversion ofbromine in R³ into hydrogen.

Step C-4 is the step of introducing an ester unit in compound 12. Thisstep is carried out by removing a proton of amido by using a base, andthen reacting the product with the following compound:

Br(CH₂)_(q)COOR¹⁵

or

Cl(CH₂)_(q)COOR¹⁵

(wherein R¹⁵ and q are defined as the same as the above). As the base,potassium carbonate, potassium t-butoxide, potassium hydroxide, sodiumhydroxide, sodium hydride, or the like is used. As a solvent, methanol,ethanol, DMF, DMSO, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step C-5 is the step of reducing ester and amido of compound 13. Thereduction is carried out by reacting compound 13 with a reducing agent.As the reducing agent, borane, a borane-tetrahydrofuran complex, aborane-dimethylsulfide complex, a sodium borohydride-boron trifluorideether complex, a sodium borohydride-boron trifluoride tetrahydrofurancomplex, or the like is preferably used. As a solvent, tetrahydrofuran,dimethoxyethane, or the like is preferably used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 120°C. The reaction time is 1 minute to 120 hours, and is usually 1 minuteto 30 hours.

Step C-6 is the step of demethylating compound 14. This step is carriedout by reacting methyl ether 14 with a Lewis acid or protonic acid. As aLewis acid, boron tribromide, boron trifluoride, boron trichloride,aluminum chloride, aluminum bromide, iron chloride, iron bromide, zincchloride, phosphorus tribromide, or the like is preferably used. As aprotonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid,hydroiodic acid, methanesulfonic acid, trifluoromethansulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid-lithiumchloride, hydrobromic acid-lithium bromide, or the like is preferablyused. As a solvent, dichloromethane, chloroform, carbon tetrachloride,water, or the like is preferably used. The reaction temperature isselected from −50 to 150° C., and is preferably −10 to 120° C. Thereaction time is 1 minute to 120 hours, and is usually 1 minute to 30hours.

Step C-7 is the step of introducing an ester unit into compound 15. Thisstep is carried out by the same method as step A-1.

Step C-8 is the step of converting a hydroxyl group of compound 16 to aleaving group. This step is carried out by the same method as step A-2.

Step C-9 is the step of thioetherifying compound 17. This step iscarried out by the same method as step A-3.

Step C-10 is the step of ester hydrolysis of compound 18. This step iscarried out by the same method as step A-4.

Step C-11 is the step of forming a salt of compound 19. This step iscarried out by the same method as step A-5.

If Of the compounds of the present invention, compounds in which A² is—(N—)—CH₂— and X is —O— can be produced by production method D.

(wherein A¹, A³, A⁴, R², R³, m, n, R¹¹, R¹² and R¹³ are defined as thesame as the above).

Step D-1 is the step of protecting a phenolic hydroxyl group by anacetyl group. This step is carried out by reacting phenol 21 with aceticanhydride or acetyl chloride in the presence of an appropriate base. Asthe base, pyridine, triethylamine, or the like is used. As a solvent,THF, DME, benzene, toluene, or the like is used, and pyridine may beused as the solvent. The reaction temperature is selected from −50 to150° C., and is preferably 0 to 50° C. The reaction time is 1 minute to120 hours, and is usually 5 minutes to 50 hours.

Step D-2 is the step of alkylating amido. Alkylation is carried out byreacting compound 22 with a base, and then reacting the product with thefollowing compound:

R²—A³—A⁴—R²

(wherein R², R¹², A³ and A⁴ are defined as the same as the above). Asthe base, sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, potassium t-butoxide, sodium t-butoxide, or the like is used.As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably 0 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours.

Step D-3 is the step of reducing amido. This step is carried out bybubbling diborane through a solution of compound 23, or adding aborane-THF solution thereto. As a solvent, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably −20 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours.

Step D-4 is the step of removing an acetyl group. This step is carriedout by dissolving compound 24 in methanol, ethanol, or the like, andthen adding an appropriate base to the resultant solution. As the base,potassium carbonate, sodium methoxide, potassium methoxide, sodiumhydroxide, potassium hydroxide, or the like is preferably used. Thereaction temperature is selected from −50 to 150° C., and is preferably0 to 50° C. The reaction time is 1 minute. to 80 hours, and is usually 5minutes to 30 hours.

Step D-5 is the step of introducing an ester unit into compound 25. Thisstep is carried out by the same method as step A-1.

Step D-6 is the step of ester hydrolysis of compound 26. This step iscarried out by the same method as step A-4.

Step D-7 is the step of forming a salt of compound 27. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A² is—(N—)—CH₂—, A³ is straight chain alkylene having 2 to 4 carbon atoms, A⁴is —S—, and X is —O— can be synthesized by production method E.

(wherein A¹, R², R³, m, R¹¹, and R¹³ are defined as the same as theabove, R¹⁶ represents chlorine, bromine, or iodine, r represents aninteger of 1 to 3, and TBS represents a t-butyldimethylsilyl group).

Step E-1 is the step of acylating compound 29. This step is carried outby reacting compound 29 with the following acid chloride in the presenceof an appropriate base:

R¹⁶(CH₂)_(r)COCl

(wherein R¹⁶ and r are defined as the same as the above). As the base,pyridine, triethylamine, or the like is used. As a solvent, methylenechloride, THF, DME, or the like is used. The reaction temperature isselected from −80 to 150° C., and is preferably −20 to 50° C. Thereaction time is 1 minute to 80 hours, and is usually 5 minutes to 30hours. This step can also be carried out by reacting compound 29 withthe following acid anhydride in the presence of an appropriate base:

(R¹⁶(CH₂)_(r)CO)₂O

(wherein R¹⁶ and r are defined as the same as the above) . As a solvent,methylene chloride, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step E-2 is the step of thioetherifying compound 30. This step iscarried out by reacting compound 30 with a sodium or potassium salt ofR²—SH (R² is defined as the same as the above) which has previously beenprepared. The sodium or potassium salt of R²—SH can be obtained byreacting R²—SH with a base such as sodium hydride, sodium carbonate,sodium t-butoxide, potassium hydride, potassium carbonate, potassiumt-butoxide, or the like. As a solvent, THF, DME, DMF, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably −20 to 100° C. The reaction time is 1 minute to 120 hours,and is usually 5 minutes to 50 hours. The step can also be carried outby adding a base such as potassium carbonate or the like to a solutionof a mixture containing compound 30 and R²—SH. In this step, at-butyldimethylsilyl group is simultaneously removed.

Step E-3 is the step of reducing amido of compound 31. This step iscarried out by the same method as step D-3.

Step E-4 is the step of introducing an ester unit into compound 32. Thisstep is carried out by the same method as step A-1.

Step E-5 is the step of ester hydrolysis of compound 33. This step iscarried out by the same method as step A-4.

Step E-6 is the step of forming a salt of compound 34. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(N—)—CH₂—, A³ is straight chain alkylene having 1 to 4 carbonatoms, R³ is hydrogen, and X is —O— can be produced by production methodF.

(wherein R², m, n, R¹¹, R¹², R¹³ and R¹⁶ are defined as the same as theabove, s represents an integer of 1 to 4, and THP represents atetrahydropyranyl group).

Step F-1 is the step of acylating methoxyaniline. This step is carriedout by reacting compound 36 with the following acid chloride in thepresence of an appropriate base:

R¹⁶(CH₂)_(m)COCl

(wherein R¹⁶ and m are defined as the same as the above). As the base,pyridine, triethylamine, or the like is used. As a solvent, methylenechloride, THF, DME, or the like is used. The reaction temperature isselected from −80 to 150° C., and is preferably −20 to 50° C. Thereaction time is 1 minute to 80 hours, and is usually 5 minutes to 30hours. This step can also be carried out by reacting compound 36 withthe following acid anhydride in the presence of an appropriate base:

(R¹⁶(CH₂)_(m)CO)₂O

(wherein R¹⁶ and m are defined as the same as the above). As a solvent,methylene chloride, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step F-2 is the step of demethylating compound 37. This step is carriedout by reacting compound 37 with boron tribromide or borontribromide-dimethylsulfide complex. As a solvent, methylene chloride,chloroform, carbon tetrachloride, or the like is used. The reactiontemperature is selected from −100 to 100° C., and is preferably −80° C.to the reflux temperature of the solvent. The reaction time is 1 minuteto 120 hours, and is usually 5 minutes to 50 hours.

Step F-3 is the step of cyclizing compound 38. This step is carried outby reacting compound 38 with an appropriate base. As the base, potassiumcarbonate, potassium t-butoxide, or the like is used. As a solvent, THF,DME, DMF, or the like is used. The reaction temperature is selected from−50 to 150° C., and is preferably 0 to 50° C. The reaction time is 1minute to 120 hours, and is usually 5 minutes to 50 hours.

Step F-4 is the step of protecting a phenol compound bytetrahydropyranyl ether. This step is carried out by reacting compound39 with dihydropyrane in the presence of an appropriate acid catalyst.As an acid catalyst, p-toluenesulfonic acid, pyridiniump-toluenesulfonate, or the like is used. As a solvent, THF, DME, DMF,methylene chloride, or the like is used. The reaction temperature isselected from −50 to 150° C., and is preferably 0 to 50° C. The reactiontime is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.

Step F-5 is the step of alkylating amide. This step is carried out byreacting compound 40 with a base, and then reacting the product with thefollowing compound:

Br (CH₂)_(s)OTHP

or

Cl(CH₂)_(s)OTHP

(wherein s and THP are defined as the same as the above). As the base,sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, potassium t-butoxide, sodium t-butoxide, or the like is used.As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably 0 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours.

Step F-6 is the step of reducing amide of compound 41. This step iscarried out by the same method as step D-3.

Step F-7 is the step of removing a tetrahydropyranyl group of compound42. This step is carried out by treating compound 42 with an appropriateacid catalyst. As the acid catalyst, p-toluenesulfonic acid, pyridiniump-toluenesulfonate, hydrochloric acid, or the like is used. As asolvent, methanol, ethanol, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step F-8 is the step of introducing an ester unit into compound 43. Thisstep is carried out by the same method as step A-1.

Step F-9 is the step of converting a hydroxyl group of compound 44 to aleaving group. This step is carried out by the same method as step A-2.

Step F-10 is the step of thioetherifying compound 45. This step iscarried out by the same method as step A-3.

Step F-11 is the step of ester hydrolysis of compound This step iscarried out by the same method as step A-4.

Step F-12 is the step of forming a salt of compound 47. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in a which A¹ is—O—, A² is —(N—)—CO—, A³ is straight chain alkylene having 1 to 4 carbonatoms, A⁴ is —S—, R³ is hydrogen, and X is —O— can be produced byproduction method G.

(wherein R², m, n, S, R¹¹, R¹², and R¹³ are defined as the same as theabove, and THP represents a tetrahydropyranyl group).

Step G-1 is the step of removing a tetrahydropyranyl group of compound41. This step is carried out by the same method as step F-7.

Step G-2 is the step of introducing an ester unit into compound 49. Thisstep is carried out by the same method as step A-1.

Step G-3 is the step of converting a hydroxyl group of compound 50 to aleaving group. This step is carried out by the same method as step A-2.

Step G-4 is the step of thioetherifying compound 51. This step iscarried out by the same method as step A-3.

Step G-5 is the step of ester hydrolysis of compound 52. This step iscarried out by the same method as step A-4.

Step G-6 is the step of forming a salt of compound 53. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(N—)—CO—, A³ is straight chain alkylene having 1 to 4 carbonatoms, R³ is hydrogen, and X is —O— can be produced by production methodH.

(wherein R², m, n, s, R¹¹, and R¹³ are defined as the same as the above,and THP represents a tetrahydropyranyl group).

Step H-1 comprises the step of alkylating amide of compound 40, and thestep of removing a tetrahydropyranyl group. The step of alkylating amideis carried out by reacting compound 40 with a base, and then reactingthe product with the following compound:

R¹²—(CH₂)_(s)—A—R²

(wherein R², R¹², A⁴, s are defined as the same as the above) As thebase, sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, potassium t-butoxide, sodium t-butoxide, or the like is used.As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably 0 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours. The step of removing atetrahydropyranyl group is carried out by the same method as step F-7.

Step H-2 is the step of introducing an ester unit into compound 55. Thisstep is carried out by the same method as step A-1.

Step H-3 is the step of ester hydrolysis of compound 56. This step iscarried out by the same method as step A-4.

Step H-4 is the step of forming a salt of compound 57. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(N—)—CO—, A³ is straight chain alkylene having 1 to 4 carbonatoms, A⁴ is —S—, R³ is hydrogen, X is —CH₂—, and n is 1 can be producedby production method I.

(wherein R², m, s, R¹¹, R¹², and R¹³ are defined as the same as theabove, and THP represents a tetrahydropyranyl group).

Step I-1 is the step of alkylating amide of compound 40. This step ofalkylating amide is carried out by reacting compound 40 with a base, andthen reacting the product with the following compound:

R¹²—(CH₂)_(s)—O—CH₂—Ph

(wherein R¹² and s are defined as the same as the above). As the base,sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, potassium t-butoxide, sodium t-butoxide, or the like is used.As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably 0 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours.

Step I-2 is the step of removing a tetrahydropyranyl group of compound59. This step is carried out by the same method as step F-7.

Step I-3 is the step of trifluoromethanesulfonylating a hydroxyl groupof compound 60. This step is carried out by reacting compound 60 with atrifluoromethanesulfonylating agent in the presence of a base. As thebase, 2,6-lutidine, pyridine, triethylamine, diisopropylamine,diisopropylethylamine, or the like is preferably used. As thetrifluoromethanesulfonylating agent, trifluoromethanesulfonic anhydride,trifluoromethanesulfonyl chloride, or the like is preferably used. As asolvent, THF, DME, dioxane, benzene, toluene, methylene chloride, DMF,or the like is used, and a base such as 2,6-lutidine, or the like may beused as the solvent. The reaction temperature is selected from −80 to150° C., and is preferably −20 to 50° C. The reaction time is 1 minuteto 80 hours, and is usually 5 minutes to 30 hours.

Step I-4 is the step of introducing an ester unit into an aromatic ringof compound 61. This step is carried out by Heck reaction of compound 61and an acrylate. As a catalyst, palladium acetate,tetrakistriphenylphosphine palladium complex, or the like is preferablyused. As a reaction additive, triphenylphosphine,tris(2-methylphenyl)phosphine, lithium chloride, or the like ispreferably used. As the base, 2,6-lutidine, pyridine, triethylamine,diisopropylamine, diisopropylethylamine, or the like is preferably used.As a solvent, THF, DME, dioxane, benzene, toluene, methylene chloride,DMF, or the like is used, and a base such as pyridine or the like may beused as the solvent. The reaction temperature is selected from −80 to150° C., and is preferably 0 to 120° C. The reaction time is 1 minute to80 hours, and is usually 5 minutes to 30 hours.

Step I-5 is the step of reducing compound 62, comprising simultaneouslyreducing a double bond and reductively removing a benzyl group. Thisstep is carried out by reducing compound 62 by a catalytic hydrogenationmethod. As a hydrogen source, hydrogen gas, formic acid, ammoniumformate, sodium formate, or the like is preferably used. As a catalyst,palladium carbon, platinum, platinum oxide, platinum carbon, palladiumacetate, a tetrakistriphenylphosphine palladium complex, or the like ispreferably used. As a solvent, methanol, ethanol, ethyl acetate, aceticacid, trifluoroacetic acid, water, tetrahydrofuran, dimethoxyethane, orthe like is preferably used. As a reaction additive, hydrochloric acid,sulfuric acid, activated carbon, iron powder, zinc powder, or the likeis preferably further used. The reaction temperature is selected from−50 to 150° C., and is preferably 0 to 120° C. The reaction time is 1minute to 120 hours, and is usually 1 minute to 30 hours.

Step I-6 is the step of converting a hydroxyl group of compound 63 to aleaving group. This step is carried out by the same method as step A-2.

Step I-7 is the step of thioetherifying compound 64. This step iscarried out by the same method as step A-3.

Step I-6 is the step of ester hydrolysis of compound 65. This step iscarried out by the same method as step A-4.

Step I-7 is the step of forming a salt of compound 66. This step iscarried out by the same method as step A-5.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(N—)—CH₂—, A³ is straight chain alkylene having 1 to 4 carbonatoms, A⁴ is —NH—, R³ is hydrogen, X is —O—, and R² is —CH₂—R¹⁷ can beproduced by production method J.

(wherein m, s, R¹¹, and R¹² are defined as the same as the above, THPrepresents a tetrahydropyranyl group, and TBS represents at-butyldimethylsilyl. R¹⁷ represents the following:

(1) -Ar (wherein Ar is phenyl, naphthyl, furyl, or thienyl (whereinphenyl, naphthyl, furyl, or thienyl may be substituted by a groupselected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxyhaving 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano,nitro, amino, and alkylamino having 1 to 5 carbon atoms); or

(2) alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbonatoms, or alkynyl having 2 to 4 carbon atoms (wherein alkyl, alkenyl, oralkynyl is substituted by one or two Ar (wherein Ar is defined as thesame as the above), and may be further substituted by a group selectedfrom —OH, —CF₃, and cycloalkyl having 3 to 8 carbon atoms)).

Step J-1 is the step of alkylating amide. This step is carried out byreacting compound 40 with a base, and then reacting the product with thefollowing compound:

Br(CH₂)_(s)OTBS

or

Cl(CH₂ )_(s)OTBS

(wherein s and TBS are defined as the same as the above). As the base,sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, potassium t-butoxide, sodium t-butoxide, or the like is used.As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like isused. The reaction temperature is selected from −50 to 150° C., and ispreferably 0 to 50° C. The reaction time is 1 minute to 120 hours, andis usually 5 minutes to 50 hours.

Step J-2 is the step of removing a TBS group of compound 68. This stepis carried out by treating compound 68 with fluorine ion. As a fluorineion source, tetrabutylammonium fluoride, potassium fluoride,hydrofluoric acid, or the like is used. As a solvent, tetrahydrofuran,dimethoxyethane, or the like is used. The reaction temperature isselected from −50 to 150° C., and is preferably 0 to 50° C. The reactiontime is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.

Step J-3 is the step of converting a hydroxyl group of compound 69 to aleaving group. This step is carried out by the same method as step A-2.

Step J-4 is the step of converting a hydroxyl group of compound 70 toazide. This step is carried out by treating compound 70 with sodiumazide. As a solvent, DMF, tetrahydrofuran, dimethoxyethane, or the likeis used. The reaction temperature is selected from −50 to 150° C., andis preferably 0 to 50° C. The reaction time is 1 minute to 120 hours,and is usually 5 minutes to 50 hours.

Step J-5 is the step of reducing compound 71. This step is carried outby the same method as step I-5.

Step J-6 is the step of acylating compound 72. This step is carried outby reacting compound 72 with a corresponding carboxylic acid in thepresence of a condensing agent. As the condensing agent,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-cyclohexyl-3-(2-morpholynoethyl)carbodiimide metho-p-toluenesufonate,or the like is preferably used. As a solvent, acetonitrile, DMF,tetrahydrofuran, dimethoxyethane, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours. Similarly to step E-1, this step can also be carried out byreacting compound 72 with an acid chloride or acid anhydride in thepresence of an appropriate base.

Step J-7 is the step of removing a tetrahydropyranyl group of compound73. This step is carried out by the same method as step F-7.

Step J-8 is the step of reducing amide of compound 74. This step iscarried out by the same method as step C-5.

Step J-9 is the step of introducing an ester unit into compound 75. Thisstep is carried out by the same method as step A-1.

Step J-10 is the step of ester hydrolysis of compound 76. This step iscarried out by the same method as step A-4.

Of the compounds of the present invention, compounds in which A¹ is—CH₂—, A² is —(N—)—CH₂—, A³ is straight chain alkylene having 1 to 4carbon atoms, R³ is hydrogen, and X is —O— can be produced by productionmethod K.

(wherein R², m, n, R¹¹, R¹², R¹³, R¹⁵, and q are defined as the same asthe above).

Step K-1 is the step of producing amide by rearrangement reaction oftetralone. This step is carried. out by reacting compound 78 with sodiumazide in trifluoroacetic acid. The reaction temperature is −20° C. tothe reflux temperature of a solvent. The reaction time is 1 minute to120 hours, and is usually 5 minutes to 50 hours.

Step K-2 is the step of protecting a phenolic hydroxyl group by anacetyl group. This step is carried out by reacting with acetic anhydrideor acetyl chloride in the presence of an appropriate base. As the base,pyridine, triethylamine, or the like is used. As a solvent, THF, DME,methylene chloride, or the like is used, and pyridine may be used as thesolvent. The reaction temperature is selected from −50 to 150° C., andis preferably 0 to 50° C. The reaction time is 1 minute to 120 hours,and is usually 5 minutes to 50 hours.

Step K-3 is the step of introducing an ester unit into amide. This stepis carried out by reacting compound 80 with the following compound inthe presence of an appropriate base:

Br(CH₂)_(q)COOR¹⁵

(wherein R¹⁵ and q are defined as the same as the above). As the base,potassium carbonate, potassium t-butoxide, potassium hydroxide, sodiumhydroxide, sodium hydride, or the like is used. As a solvent, methanol,ethanol, DMF, DMSO, THF, DME, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 50°C. The reaction time is 1 minute to 120 hours, and is usually 5 minutesto 50 hours.

Step K-4 is the step of reducing ester and amidoe and removing an acetylgroup at the same time. This step is carried out by reacting compound 81with lithium aluminum hydride. As a solvent, THF, DME, ether, or thelike is used. The reaction temperature is −40° C. to the refluxtemperature of the solvent. The reaction time is 1 minute to 120 hours,and is usually 5 minutes to 50 hours.

Step K-5 is the step of introducing an ester unit into compound 82. Thisstep is carried out by the same method as step A-1.

Step K-6 is the step of converting a hydroxyl group of compound 83 to aleaving group. This step is carried out by the same method as step A-2.

Step K-7 is the step of thioetherifying compound 84. This step iscarried out by the same method as step A-3.

Step K-8 is the step of ester hydrolysis of compound 85. This step iscarried out by the same method as step A-4.

Step K-9 is the step of forming a salt of compound 86. This step iscarried out by the same method as step A-5.

Of the starting raw materials of the production method E, compounds inwhich A¹ is —CH₂—, m is 1, and R³ is hydrogen can be produced byproduction method L.

(wherein TBS represents a t-butyldimethylsilyl group).

Step L-1 is the step of protecting a hydroxyl group of quinoline by at-butyldimethylsilyl group. This step is carried out by reactingcompound 88 with t-butyldimethylsilylchloride in the presence of anappropriate base. As the base, imidazole is preferably used. As asolvent, DMF, THF, or the like is used. The reaction temperature isselected from −50 to 150° C., and is preferably 0 to 50° C. The reactiontime is 1 minute to 80 hours, and is usually 5 minutes to 30 hours.

Step L-2 is the step of reducing quinoline to tetrahydroquinoline, andperformed under conventional conditions for hydrogenation. This step iscarried out by using a catalyst such as palladium-carbon, Raney nickel,or the like under a hydrogen atmosphere at a pressure of 1 to 10 atm. Asa solvent, methanol, ethanol, THF, ethyl acetate, benzene, or the likeis used. The reaction temperature is selected from −50 to 150° C., andis preferably 0 to 50° C. The reaction time is 1 minute to 120 hours,and is usually 5 minutes to 50 hours.

Of the compounds of the present invention, compounds in which A¹ is —O—,A² is —(CH—)—, A³ is —CH₂CH₂—, A⁴ is —S—, R³ is hydrogen, X is —O—, andm is 1 can be produced by production method M.

Step M-1 is the step of reducing benzofuran to dihydrobenzofuran. Thisstep is carried out by using a catalyst such as palladium-carbon, Raneynickel, or the like under a hydrogen atmosphere at a pressure of 1 to 10atm., and reaction is accelerated by adding an acid such as acetic acid,hydrochloric acid, or the like. As a solvent, methanol, ethanol, THF,ethyl acetate, benzene, or the like is used. The reaction temperature isselected from −50 to 150° C., and is preferably 0 to 50° C. The reactiontime is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.

Step M-2 is the step of thioetherifying compound 92. This step iscarried out by the same method as step A-3.

Step M-3 is the step of ester hydrolysis of compound 93. This step iscarried out by the same method as step A-4.

Step M-4 is the step of forming a salt of compound 94. This step iscarried out by the same method as step A-5.

(wherein R², n, R¹¹ and R¹³ are defined as the same as the above).

Of the compounds of the present invention, optically active compounds inwhich A¹ is —O—, A² is —(CH—)—, A³ is —CH₂CH₂—, A⁴ is —S—, R³ ishydrogen, X is —O—, and m is 1 can be produced by production method N.

(wherein R², n, R¹¹, R¹², R¹³ and R¹⁴ are defined as the same as theabove, and R¹⁸ represents an optically active amine cation).

Step N-1 is the step of introducing an ester unit into a phenolichydroxyl group of compound 96. This step is carried out by the samemethod as step A-1.

Step N-2 is the step of reducing benzofuran of compound 97 todihydrobenzofuran. This step is carried out by the same method as stepM-1.

Step N-3 is the step of ester hydrolysis of compound 98. This step iscarried out by the same method as step A-4.

Step N-4 is the step of optical resolution of compound 99, comprising asalt formation step and a resolution step. The salt formation step iscarried out by reacting compound 99 with an optically active amine. Asthe optically active amine, 1-(1-naphthyl)ethylamine,2-(benzylamino)cyclohexane methanol, cinchonine, or the like ispreferably used. As a solvent, water, methanol, ethanol,tetrahydrofuran, ethyl acetate, or the like is used. The reactiontemperature is selected from −50 to 150° C., and is preferably 0 to 80°C. The reaction time is 1 minute to 120 hours, and is usually 1 minuteto 30 hours. The resolution step is carried out by dissolving anoptically active amine salt of compound 99 under heating, and thenstanding it to cool. Crystallization may be accelerated by adding a seedcrystal. As a solvent, water, methanol, ethanol, tetrahydrofuran, ethylacetate, or the like is used.

N-5 is the step of esterifying compound 100. This step is carried out byrefluxing compound 100 with alcohol under acidic conditions. As an acid,sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid,methanesulfonic acid, trifluoromethanesulfonic acid, or the like isused. As a solvent, benzene, toluene, or the like is used, and alcoholmay be used as the solvent. Furthermore, a dehydrating agent may beadded, or a dehydrating device such as Dean-stark or the like may beused. The reaction temperature is selected from 0 to 150° C., andreaction is preferably effected under reflux conditions of the solvent.The reaction time is 1 minute to 120 hours, and is usually 5 minutes to50 hours

Step N-6 is the step of converting a hydroxyl group of compound 101 to aleaving group. This step is carried out by the same method as step A-2.

Step N-7 is the step of thioetherifying compound 102. This step iscarried out by the same method as step A-3.

Step N-8 is the step of ester hydrolysis of compound 103. This step iscarried out by the same method as step A-4.

Step N-9 is the step of forming a salt of compound 104. This step iscarried out by the same method as step A-5.

With the compounds of the present invention having asymmetric carbons,the formula represents d, l and dl isomers. Each of the steps can beapplied to the d, l and dl isomers in the same manner.

In producing dl isomers of the compounds of the present invention,compounds represented by formula (I), which are obtained in a racemicmodification, can easily be separated into d and l isomers by anoptically active column chromatography technique.

The compounds of the present invention have the strong TXA₂ receptorantagonistic action and PGI₂ receptor agonistic action, and thus havepharmacological actions such as the platelet aggregation inhibitingaction, vascular contraction inhibiting action, bronchial contractioninhibiting action, etc. Therefore, these compounds are effective totreat or prevent diseases such as hypertension, thrombosis, ischemicheart diseases (myocardial infarction, angina pectoris, thrombogenesisafter PTCA, etc.), cerebral circulatory disorders (cerebral infarction,transient cerebral ischemic attack, etc.), peripheral circulatorydisorders (Buerger's disease, Raynaud's disease, Behcet's disease,thrombotic thrombocytopetic purpura, hepatic disorders, renal disorders,etc.), arteriosclerosis, platelet functional disorder concurrent withdiabetes, hyperlipidemia, nephritis, asthma, allergic diseases, etc.

For this purpose, the compounds of the present invention can begenerally administered by intravenous injection, intraarterialinjection, intramuscular injection, percutaneous administration,subcutaneous administration, or oral administration. In general oral orrectal administration, the compound is administered 1 to 4 times a dayat a dose of 1 μg/kg/day to 100 mg/kg/day. In intravenous infusion orintraarterial injection, the compound is administered at a dose of 1ng/kg/min to 1 mg/kg/min to obtain good results. In general intravenousinjection, intraarterial injection, intramuscular injection, orsubcutaneous administration, the compound is administered 1 to 4 times aday at a dose of 0.1 μg/kg/day to 100 mg/kg/day. In theseadministrations, a dose is selected from the above-described ranges inconsideration of the age, sexuality, and conditions of a patient, andthe times of administration of the compound, etc.

The compounds of the present invention can be orally administered in asolid form containing starch, lactose, sucrose, glucose, crystallinecellulose, an excipient such as a type of clay, a colorant, a lubricant,a binder, a disintegrant, and a coating agent. The compounds of thepresent invention may be parenterally administered in the form of asterilized solution, and may also contain other solutes such as atonicity agent such as sodium chloride, glucose, or the like, a PHregulator, and solution adjuvant such as cyclodextrin or the like. Thecompounds of the present invention have stability in chemical structure,and thus cause no difficulties in formulation, thereby permitting avariety of administration methods such as oral formulations (tablets,powder, and granules), various injections, suppositories, ointments,lotions, etc.

EXAMPLES

The present invention will be described in further detail below withreference to examples.

Reference Example 1 4-bromo-2-nitro-6-methoxyphenol

Trifluoroacetic anhydride (3.50 ml) was cooled to −78° C. 61% nitricacid (1.85 ml) was slowly added dropwise at −78° C., and the resultantmixture was stirred at 0° C. for 2.5 hours. The above nitrating agentwas added to a solution of 4-bromoguaiacol (5.00 g) in ethyl acetate (50ml) and the mixture was stirred at 0° C. for 1.5 hours. Saturated brinewas added to the reaction solution, and an organic layer was thenseparated. The organic layer was washed with water and saturated brine,dried over magnesium sulfate, concentrated, and then allowed to cool toform crystals. After filtration, the crystal was washed with a smallamount of n-hexane, and then dried under reduced pressure to obtain theobject compound (4.02 g, yield 66%).

Pale yellow needle crystals: mp. 113-114° C. (recrystallized from ethylacetate)

¹H-NMR (300 MHz, CDCl₃) δ3.96 (3H, s), 7.21 (1H, d, J=2.2 Hz), 7.86 (1H,d, J=2.2 Hz).

IR (KBr method) 3192, 3093, 1537, 1316, 1259, 1153, 1049, 915, 702, 676cm⁻¹

Mass (EI, m/e) 247, 249 (M⁺) (peak height 1:1)

Reference Example 2 Methyl 4-bromo-2-nitro-6-methoxyphenoxyacetate

4-bromo-2-nitro-6-methoxyphenol (52.2 g) was dissolved in DMF (450 ml),and methyl bromoacetate (30 ml) and potassium carbonate (41.5 g) wereadded to the solution, and the mixture was stirred at room temperaturefor 14 hours. The reaction solution was subjected to suction filtrationto remove inorganic salts, and the residue was washed with a smallamount of ethyl acetate. The filtrate was concentrated, and ethanol wasadded to the residue to crystallize. After filtration, the crystal waswashed with small amounts of water and ethanol, and then dried underreduced pressure to obtain the object compound (50.54 g, it yield 75%).

Colorless needle crystals: mp. 130-130.5° C. (recrystallized fromethanol)

¹H-NMR. (300 MHz, CDCl₃) δ3.79 (3H, s), 3.91 (3H, s), 4.76 (2H, s), 7.22(1H, d, J=2.2 Hz), 7.52 (1H, d, J=2.2 Hz).

IR (KBr method) 3085, 3033, 2992, 2955, 1760, 1595, 1538, 1481, 1444,1361, 1260, 1205, 1176, 1053, 856, 696 cm⁻¹

Mass (EI, m/e) 319, 321 (M⁺) (peak height=1:1)

Reference Example 3 8-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

Methyl 4-bromo-2-nitro-6-methoxyphenoxyacetate (897 mg), Zn (50 mg),activated carbon (130 mg), and 10% Pd/C (containing 50% water) (50 mg)were suspended in acetic acid (10 ml), and the resultant suspension wasstirred at 70° C. for 7.5 hours in a hydrogen atmosphere. Thetemperature was returned to room temperature, and an aqueous solutionobtained by dissolving sodium acetate (250 mg) in water (1.0 ml) wasthen added to the reaction solution. The mixture was filtered with amembrane filter, and the residue was washed with a small amount of ethylacetate. The filtrate was evaporated, and water was added to the residueto crystallize. After filtration, the crystal was dried under reducedpressure to obtain the object compound (470 mg, yield 94%).

Colorless needle crystals: mp. 186-187° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ3.90 (3H, s), 4.68 (2H, s), 6.45 (1H, dd,J=1.5, 8 Hz), 6.65 (1H, dd, J=1.5, 8 Hz), 6.92 (1H, t, J=8 Hz), 9.19(1H, bs).

IR (KBr method) 3052, 3006, 2938, 1696, 1615, 1518, 1489, 1437, 1402,1282, 1249, 1216, 1172, 1120, 1031, 774, 723 cm⁻¹

Mass (EI, m/e) 179 (M⁺)

Reference Example 4 Methyl8-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzooxazine-4-ylacetate

8-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.00 g) and potassiumcarbonate (1.85 g) were suspended in DMF (4.0 ml), and methylbromoacetate (1.20 ml) was added to the resultant suspension, and themixture was stirred at room temperature for 18.5 hours. The reactionsolution was subjected to suction filtration to remove inorganic salts,and the residue was washed with a small amount of ethyl acetate. Water(10 ml) and saturated brine (10 ml) were added to the filtrate, and theresulting mixture was then extracted with ethyl acetate. The resultantorganic layer was washed with water and saturated brine, dried overmagnesium sulfate, and then evaporated. The residue was recrystallizedfrom ethyl acetate/n-hexane to obtain the object compound (2.58.g, yield92%).

Colorless leaf-like crystals: mp. 118-119° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ3.78 (3H, s), 3.91 (3H, s), 4.67 (2H, s), 4.74(2H, s), 6.41 (1H, dd, J=1, 8 Hz), 6.71 (1H, dd, J=1, 8 Hz), 6.97 (1H,t, J=8 Hz).

IR (KBr method) 2966, 1746, 1680, 1487, 1429, 1404, 1209, 1166, 1052cm⁻¹

Mass (El, m/e) 251 (M⁺)

Reference Example 54-(2-hydroxyethyl)-8-methoxy-3,4-dihydro-2H-1,4-benzoxazine

Methyl 8-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzooxazine-4-ylacetate (4.52g) and sodium borohydride (1.10 g) were suspended in THF (10 ml), andthe resultant suspension was cooled to 0° C. Atrifluoroboron-tetrahydrofuran complex (4.0 ml, 2.0 eq) was slowly addeddropwise to the suspension. After heat generation stopped, thetemperature was returned to room temperature, and the reaction solutionwas further stirred at 70° C. for 22 hours. The reaction solution wasthen cooled to 0° C., and water was added thereto to terminate reaction.Then, the reaction solution was rendered basic with sodium carbonate,and extracted with ethyl acetate. The resultant organic layer was washedwith water, saturated sodium bicarbonate solution, and saturated brine,dried over magnesium sulfate, and then evaporated. The residue wasrecrystallized from ethyl acetate/n-hexane to obtain the object compound(3.37 g, yield 89%).

Colorless prismatic crystals: mp. 59-60° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.79 (1H, t, J=5 Hz), 3.42 (4H, m), 3.83 (2H,q, J=5 Hz), 3.86 (3H, s), 4.31 (2H, m), 6.38 (1H, dd, J=1.5, 8 Hz), 6.45(1H, dd, J=1.5, 8 Hz), 6.78 (1H, t, J=8 Hz).

IR (KBr method) 3259, 2931, 2871, 1610, 1500, 1460, 1347, 1273, 1248,1204, 1138, 1064, 762, 717 cm⁻¹

Mass (EI, m/e) 209 (M⁺)

Reference Example 64-(2-hydroxyethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine

A solution of4-(2-hydroxyethyl)-8-methoxy-3,4-dihydro-2H-1,4-benzoxazine (20.70 g) indichloromethane (350 ml) was cooled to −78°. Boron tribromide (42.09 g)was added dropwise to the solution over 20 minutes, and the resultantmixture was stirred at room temperature for 1.5 hours. An aqueoussolution of sodium hydroxide was added to the reaction solution, and themixture was rendered basic with a saturated sodium bicarbonate solution,and then extracted with ethyl acetate. The resultant organic layer waswashed with water and saturated brine, dried over magnesium sulfate, andthen evaporated to obtain the object compound (15.55 g, yield 81%).

Colorless plate crystals: mp. 105.5° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, DMSO-d₃) δ3.26 (1H, t, J=5.5 Hz), 3.36 (2H, t, J=4 Hz),3.54 (2H, q, J=5.5 Hz), 4.10 (2H, t, J=4 Hz), 4.65 (1H, t, J=5.5 Hz),6.07 (1H, dd, J=1, 8 Hz), 6.15 (1H, dd, J=1, 8 Hz), 6.49. (1H, t, J=8Hz), 8.49 (1H, s).

IR (KBr method) 3486, 3250, 2950, 2880, 1615, 1584, 1512, 1483, 1460,1350, 1272, 1253, 1201, 1166, 1125, 1054, 980, 930, 901, 876, 832, 795,766, 712 cm⁻¹

Mass (EI, m/e) 195 (M⁺)

Reference Example 7 Methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

4-(2-(hydroxyethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (4.66 g)was dissolved in anhydrous DMF (50 ml), and anhydrous potassiumcarbonate (8.50 g) and methyl bromoacetate (4.0 ml) were added to theresultant solution, and the mixture was stirred at room temperature for6 hours. The solvent was distilled off, and the residue was poured into5% citric acid, and then extracted with ethyl acetate. The resultantorganic layer was washed with water and saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was recrystallizedfrom ethyl acetate/n-hexane to obtain the object compound (3.83 g, yield60%).

Colorless plate crystals: mp. 64-66° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.78 (1H, t, J=5.5 Hz), 3.42 (4H, m), 3.79 (3H,s), 3.83 (2H, q, J=5.5 Hz), 4.31 (2H, m), 4.68 (2H, s), 6.26 (1H, dd,J=1, 8 Hz), 6.47 (1H, dd, J=1, 8 Hz), 6.73 (1H, t, J=8 Hz).

IR (Kbr method) 3484, 2904, 2864, 1719, 1615, 1510, 1489, 1446, 1433,1381, 1350; 1321, 1274, 1257, 1232, 1214, 1193, 1145, 1094, 1069, 1054,1040, 1015, 973, 650, 602 cm⁻¹

Mass (El, m/e) 267 (M⁺)

Reference Example 8 2,3-dimethoxy-α-chloroacetoanilide

2,3-dimethoxyaniline (1.00 g) and chloroacetic anhydride (1.26 g) weredissolved in THF (5 ml), and the resultant solution was stirred at roomtemperature for 4 hours. The solvent was distilled off under reducedpressure, and the reaction solution was then poured into a saturatedsodium bicarbonate solution, and extracted with ethyl acetate. Theresultant organic layer was washed with saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified bycolumn chromatography (silica gel; ethyl acetate/n-hexane=1:2) to obtainthe object compound (1.64 g, yield 97%).

Colorless leaf-like crystals: mp. 58-59° C. (recrystallized fromdichloromethane/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ3.88 (3H, s), 3.91 (3H, s), 4.20 (2H, s), 6.73(1H, dd, J=1.5, 8.5 Hz), 7.06 (1H, t, J=8.5 Hz), 7.96 (1H, dd, J=1.5,8.5 Hz), 9.05 (1H, bs).

IR (KBr method) 3324, 3008, 2952, 1702, 1607, 1549, 1481, 1462, 1423,1400, 1332, 1296, 1259, 1224, 1187, 1176, 1166, 1083, 990, 967, 779,743, 681 cm⁻¹

Mass (EI, m/e) 229, 231 (M⁺) (peak height=3:1)

Reference Example 9 8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

A solution of 2,3-dimethoxy-α-chloroacetoanilide (1.43 g) indichloromethane (30 ml) was cooled to −78° C., and a solution (13.0 ml)of 1.0M boron tribromide in dichloromethane was added to the solution,and the mixture was stirred at 0° C. for 2 hours. The reaction solutionwas poured into water, and then extracted with ethyl acetate. Theresultant organic layer was washed with water and saturated saline,dried over magnesium sulfate, and then concentrated. The residue wasdissolved in anhydrous DMF (30 ml), and potassium carbonate (1.03 g) wasadded to the resultant solution, and the mixture was stirred for 2.5hours. The solvent was distilled off under reduced pressure, and theresidue was poured into 5% citric acid, and then extracted with ethylacetate. The resultant organic layer was washed with water and saturatedbrine, dried over magnesium sulfate, and then concentrated. The residuewas recrystallized from ethyl acetate to obtain the object compound (922mg, yield 90%).

Colorless plate crystals: mp. 226° C. (recrystallized from ethylacetate)

¹H-NMR (300 MHz, DMSO-d₆) δ4.49 (2H, s), 6.34 (1H, dd, J=1, 8 Hz), 6.45(1H, dd, J=1, 8 Hz), 6.71 (1H, t, J=8 Hz), 9.37 (1H, bs), 10.57 (1H,bs).

IR (KBr method) 3200, 1682, 1638, 1609, 1504, 1450, 1226, 1205, 1187,1071, 785 cm⁻¹

Mass (EI, m/e) 165 (M⁺)

Reference Example 103-oxo-8-(tetrahydropyrane-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzooxazine (740 mg) was dissolvedin anhydrous DMF (1.5 ml), and dihydropyrane (1.0 g) and pyridiniump-toluenesulfonate (360 mg) were added to the-resultant solution, andthe mixture was stirred at room temperature for 18 hours. The solventwas distilled off under reduced pressure, and the residue was pouredinto a saturated sodium bicarbonate aqueous solution, and then extractedwith ethyl acetate. The resultant organic layer was washed with water,5% citric acid, water, and saturated brine, dried over magnesiumsulfate, and then concentrated. The residue was recrystallized fromethyl acetate to obtain the object compound (890 mg, yield 80%).

Colorless plate crystals: mp. 186° C. (recrystallized from ethylacetate)

¹H-NMR (300 MHz, DMSO-d₆) δ1.54 (3H, m), 1.76 (3H, m), 3.52 (¹H, m),3.79 (1H, m), 4.54 (2H, s), 5.40 (1H, t, J=4 Hz), 6.54 (1H, dd, J=1.5, 8Hz), 6.76 (1H, dd, J=1.5, 8 Hz), 6.83 (1H, t, J=8 Hz), 10.67 (1H, bs).

IR (KBr method) 3104, 3080, 3008, 2944, 2892, 1684, 1615, 1520, 1495,1452, 1406, 1354, 1288, 1253, 1214, 1207, 1180, 1125, 1087, 1048, 1036,1021, 949, 917, 884, 814, 764 cm⁻¹

Mass (EI, m/e) 249 (M⁺)

Reference Example 114-(2-(tetrahydropyran-2-yloxy)ethyl)-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

Sodium hydride (1.02 g) was washed with n-hexane, dried under reducedpressure, and the air was substituted by argon. A solution of3-oxo-8-tetrahydropyranyloxy-3,4-dihydro-2H-1,4-benzoxazine (6.04 g) inanhydrous DMF (100 ml) was added to the sodium hydride, and the mixturewas stirred at room temperature for 1 hour.2-(2-bromoethoxy)tetrahydropyrane (7.60 g) was added to the resultantmixture, and the mixture was stirred at room temperature for 17.5 hours.The solvent was distilled off under reduced pressure, and the residuewas poured into a 5% citric acid aqueous solution, and then extractedwith ethyl acetate. The resultant organic layer was washed with waterand saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was dissolved in THF (150 ml), and a 1.0Mborane THF solution (60 ml) was added to the resultant solution, and themixture was stirred at room temperature for 2 hours. A saturated sodiumbicarbonate aqueous solution was added to the resultant solution toterminate reaction, and the reaction solution was extracted with ethylacetate. The resultant organic layer was washed with water and saturatedbrine, dried over magnesium sulfate, and then concentrated. The residuewas purified by medium-pressure column chromatography (silica gel; ethylacetate/n-hexane=1:2) to obtain the object compound (7.01 g, yield 93%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.50-2.10 (12H, m), 3.47 (5H, m), 3.62 (2H, m),3.82 (1H, m), 3.91 (1H, m), 4.03 (1H, m), 4.25 (2H, t, J=4.5 Hz), 4.59(1H, t, J=3 Hz), 5.36 (1H, t, J=3 Hz), 6.41 (1H, dd, J=1, 8 Hz), 6.52(1H, dd, J=1, 8 Hz), 6.72 (1H, t, J=8 Hz).

IR (liquid film method) 2944, 2874, 1609, 1485, 1350, 1251, 1203, 1181,1123, 1077, 1035, 996 cm⁻¹

Mass (El, m/e) 363 (M⁺)

Reference Example 124-(2-hydroxyethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine

4-(2-(tetrahydropyran-2-yloxy)ethyl)-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzooxazine(3.89 g) was dissolved in methanol (80 ml), and pyridiniump-toluenesulfonate (520 mg) was added to the resultant solution, and themixture was stirred at room temperature for 1.5 hours. The solvent wasdistilled off under reduced pressure, and the residue was poured into 5%citric acid, and then extracted with ethyl acetate. The resultantorganic layer was washed with water and saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was recrystallizedfrom ethyl acetate/n-hexane to obtain the object compound (2.00 g, yield97%).

Colorless plate crystal: mp. 105.5° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, DMSO-d₆) δ3.26 (2H, t, J=5.5 Hz), 3.36 (2H, t, J=4Hz)), 3.54 (2H, q, J=5.5 Hz), 4.10 (2H, t, J=4 Hz), 4.65 (1H, t, J=5.5Hz)), 6.07 (1H, dd, J=1, 8 Hz), 6.15 (1H, dd, J=1, 8 Hz), 6.49 (1H, t,J=8 Hz), 8.49 (1H, s).

IR (KBr method) 3486, 3250, 2950, 2880, 1615, 1584, 1512, 1483, 1460,1350, 1272, 1253, 1201, 1166, 1125, 1054, 980, 930, 901, 876, 832, 795,766, 712 cm⁻¹

Mass (EI, m/e) 195 (M⁺)

Reference Example 134-(2-hydroxyethyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

Sodium hydride (127 mg) was washed with n-hexane, dried under reducedpressure, and the air was substituted by argon. A solution of3-oxo-(8-tetrahydropyrane-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (529mg) in anhydrous DMF (15 ml) was stirred into the sodium hydride, andthe mixture was stirred at room temperature for 10 minutes.2-(2-bromoethoxy)tetrahydropyrane (935 mg) was dissolved in DMF (3.0ml), and the resultant solution was added to the resultant mixture, andthe mixture was stirred at room temperature for 5.5 hours. The solventwas distilled off under reduced pressure, and the residue was pouredinto a 5% citric acid aqueous solution, and then extracted with ethylacetate. The resultant organic layer was washed with water and saturatedbrine, dried over magnesium sulfate, and then concentrated. The residuewas dissolved in methanol (50 ml), and p-toluenesulfonic acid hydrate(160 mg) was added to the resultant solution, and the mixture wasstirred at room temperature for 2 hours. The solvent was distilled offunder reduced pressure, and the residue was poured into 5% citric acid,and then extracted with ethyl acetate. The resultant organic layer waswashed with water and saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was recrystallized from ethylacetate/n-hexane to obtain the object compound (415 mg, yield 94%).

Colorless plate crystal: mp. 166° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, DMSOd₆) δ3.54 (2H, m), 3.90 (2H, t, J=6 Hz), 4.55 (2H,s), 4.85 (1H, br), 6.55 (1H, dd, J=1, 8 Hz), 6.70 (1H, dd, J=1, 8 Hz),6.70 (1H, dd, J=1, 8 Hz), 6.82 (1H, t, J=8 Hz), 9.42 (1H, bs).

IR (KBr method) 3334, 1669, 1647, 1607, 1497, 1427, 1230, 1048, 727 cm⁻¹

Mass (EI, m/e) 209 (M⁺)

Reference Example 14Methyl(4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Reference Example 7 was repeated by except that4-(2-hydroxyethyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (216mg) was used to obtain the object compound (280 mg, yield 97%).

Colorless plate crystal: mp. 106° C. (recrystallized fromethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.13 (1H, bs), 3.80 (3H, s), 3.94 (2H, bt,J=5.5 Hz)), 4.13 (2H, t, J=5.5 Hz), 4.70 (2H, s), 4.72 (2H, s), 6.62(1H, dd, J=1, 8 Hz), 6.80 (1H, dd, J=1, 8 Hz), 6.96 (1H, t, J=8 Hz).

IR (KBr method) 3376, 2962, 2914, 2856, 1763, 1742, 1663, 1613, 1504,1489, 1410, 1272, 1220, 1158, 1071, 1054, 1002, 785, 774 cm⁻¹

Mass (EI, m/e) 281 (M⁺)

Reference Example 15 8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (100 mg) was dissolved intoluene (2 ml), and acetic anhydride (0.09 ml) and pyridine (2 ml) wereadded to the resultant solution at room temperature, and the mixture wasstirred for 1.5 hours. The reaction solution was poured into a 1-Nhydrochloric acid aqueous solution, and then extracted with ethylacetate. The resultant organic layer was washed with water and saturatedbrine, dried over sodium sulfate, and then concentrated. The residue wasrecrystallized from ethyl acetate to obtain the object compound (97 mg,yield 77%). ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.11 (3H, s), 4.61 (2H, s), 6.71 (1H, dd,J=8.0, 1.4 Hz)), 6.76 (1H, dd, J=8.0, 1.4 Hz), 6.94 (1H, t, J=8.0 Hz),8.67 (1H, bs).

IR (KBr method) 3054, 1771, 1694, 1620, 1518, 1495, 1448, 1410, 1381,1249, 1226, 1199, 1166, 1067, 901, 779 cm⁻¹

Mass (EI, m/e) 207 (M⁺)

Reference Example 168-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

Anhydrous THF (15 ml) was added to sodium hydride (106 mg) to form asuspension, and a solution of8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (498 mg) in anhydrous DMF(5 ml) was added to the resulting suspension, and the mixture wasstirred at room temperature for 1 hour. 2-diphenylmethoxyethyl bromide(980 mg) was added to the mixture, and the mixture was stirred at roomtemperature overnight. The reaction solution was poured into a 3% citricacid aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was washed with water and saturated brine, driedover sodium sulfate, and then concentrated. The residue was purified bymedium-pressure column chromatography (solvent:ethylacetate/cyclohexane=1/3) to obtain the colorless oily object compound(640 mg, yield 66%).

¹H-NMR (300 MHz, CDCl₃) δ2.33 (3H, s), 3.72 (2H, t, J=5.8 Hz), 4.17 (2H,t, J=5.8 Hz), 4.54 (2H, s), 5.34 (1H, s), 6.79 (1H, dd, J=8.2, 1.4 Hz)),6.99 (1H, t, J=8.2 Hz), 7.18 (1H, dd, J=8.2, 1.4 Hz), 7.18-7.32 (10H,m).

IR (liquid film method) 3064, 3030, 2872, 1769, 1684, 1613, 1495, 1456,1404, 1371, 1332, 1305, 1262, 1195, 1178, 1141, 1102, 1079, 1025, 1002,911 cm⁻¹

Mass (EI, m/e) 417 (M⁺)

Reference Example 178-acetoxy-4-(2-(1,1-diphenylethoxy)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

A solution of 2-(1,1-diphenylethoxy)-ethanol (606 mg) in THF (10 ml) wascooled to −40° C. n-butyllithium (1.47M hexane solution) (2.6 ml) andtoluenesulfonyl chloride (715 mg) were added to the solution, and themixture was stirred for 1.5 hours. The reaction solution was poured intowater, and then extracted with ethyl acetate. The resultant organiclayer was washed with water and saturated brine, dried over sodiumsulfate, and concentrated to obtain a tosyl compound.

Anhydrous DMF (5 ml) was added to sodium hydride (84 mg) to form asuspension, and a solution of8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzooxazine (363 mg) in anhydrousDMF (5 ml) was stirred into the resulting suspension, and the mixturewas stirred at room temperature for 30 minutes. The above tosyl compoundwas added to this mixture, and the mixture was stirred at roomtemperature overnight. The reaction solution was poured into a 5% citricacid aqueous solution, and then extracted with ethyl acetate containing15% n-hexane. The resultant organic layer was washed with water andsaturated brine, dried over sodium sulfate, and then concentrated. Theresidue was purified by medium-pressure column chromatography(solvent:ethyl acetate/cyclohexane=1/4) to obtain the colorless oilyobject compound (429 mg, yield 57%).

¹H-NMR (300 MHz, CDCl₃) δ1.81 (3H, s), 2.32 (3H, s), 3.52 (2H, t, J=5.8Hz), 4.12 (2H, t, J=5.8 Hz), 4.53 (2H, s), 6.77 (1H, dd, J=8.2, 1.4 Hz),6.94 (1H, t, J=8.2 Hz), 7.04 (1H, dd, J=8.2, 1.4 Hz), 7.18-7.29 (10H,m).

IR (KBr method) 3408, 1773, 1688, 1613, 1497, 1483, 1218, 1199, 1174,1139 cm⁻¹

Mass (EI, m/e) 431 (M⁺)

Reference Example 188-acetoxy-4-(4,4-diphenylpentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

Pyridine (3 ml) and p-toluenesulfonyl chloride (300 mg) were added to asolution of 4,4-diphenylpentane-1-ol (391 mg) in dichloromethane (10ml), and the mixture was stirred for 1.5 hours. The reaction solutionwas poured into 1-N hydrochloric acid, and then extracted with ethylacetate. The resultant organic layer was washed with water and saturatedbrine, dried over sodium sulfate, and concentrated to obtain a tosylcompound.

Anhydrous DMF (5 ml) was added to sodium hydride (85 mg) to form asuspension, and a solution of3-oxo-8-acetoxy-3,4-dihydro-2H-1,4-benzoxazine (507 mg) in anhydrous DMF(5 ml) was added to the resultant suspension, and the mixture wasstirred at 0° C. for 40 minutes. A solution of the obtained tosylcompound in anhydrous DMF (2 ml) was added to the mixture, and themixture was stirred at room temperature for 7 hours. The reactionsolution was poured into a 5% citric acid aqueous solution, and thenetracted with ethyl acetate containing 15% n-hexane. The resultantorganic layer was washed with water and saturated brine, dried oversodium sulfate, and then concentrated. The residue was purified bymedium-pressure column chromatography (solvent:ethylacetate/cyclohexane=1/6) to obtain the object compound (428 mg, yield61%).

¹H-NMR (300 MHz, CDCl₃) δ1.42-1.55 (4H, m), 1.61 (3H, s), 2.14-2.24 (2H,m), 2.31 (3H, s), 3.83 (2H, t, J=7.7 Hz), 4.55 (2H, s), 6.46 (1H, dd,J=8.2, 1.4 Hz), 6.74 (1H, dd, J=8.2, 1.4 Hz), 6.87 (1H, t, J=8.2 Hz),7.13-7.21 (6H, m), 7.21-7.30 (4H, m).

IR (KBr method) 1688, 1611, 1495, 1481, 1446, 1408, 1375, 1328, 1299,1261, 1224, 1205, 1183, 1137, 1042, 1029, 777, 748, 739, 698 cm⁻¹

Mass (EI, m/e) 429 (M⁺)

Reference Example 198-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine

8-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzooxazine(630 mg) was dissolved in THF (10 ml), and a 1.0M borane THF solution(4.5 ml) was added to the resultant solution at 0° C., followed bystirring at room temperature for 4 hours. After water was added to thereaction solution to terminate reaction, the reaction solution wasextracted with ethyl acetate. The resultant organic layer was washedwith water, saturated sodium bicarbonate water, water and saturatedbrine, dried over sodium sulfate, and then concentrated. The residue waspurified by medium-pressure column chromatography (solvent:ethylacetate/cyclohexane=1/5) to obtain the colorless oily object compound(550 mg, yield 90%).

¹H-NMR (300 MHz, CDCl₃) δ2.30 (3H, s), 3.47 (2H, t, J=4.5 Hz), 3.54 (2H,t, J=5.5 Hz), 3.65 (2H, t, J=5.5 Hz), 4.18 (2H, t, J=4.5 Hz), 5.35 (1H,s), 6.38 (1H, dd, J=8.2, 1.4 Hz), 6.49 (1H, dd, J=8.2, 1.4 Hz), 6.73(1H, t, J=8.2 Hz), 7.19-7.33 (10H, m).

IR (liquid film method) 3064, 3030, 2926, 2868, 1763, 1613, 1582, 1483,1456, 1369, 1311, 1168, 1015 cm⁻¹

Mass (EI, m/e) 403 (M⁺)

Reference Example 204-(2-(diphenylmethoxy)ethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine

8-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine(482 mg) was dissolved in THF (2 ml) and a methanol (10 ml), andanhydrous potassium carbonate (250 mg) was added to the resultantsolution, and the mixture was stirred at room temperature for 1 hour.The solvent was distilled off under reduced pressure, and the residuewas poured into 5% citric acid, and then extracted with ethyl acetate.The resultant organic layer was washed with water and saturated brine,dried over sodium sulfate, and then concentrated to obtain the colorlessoily object compound (429 mg, yield 99%).

¹H-NMR (300 MHz, CDCl₃) δ3.48 (2H, t, J=4.5 Hz), 3.53 (2H, t, J=5.5 Hz),3.65 (2H, t, J=5.5 Hz), 4.23 (2H, t, J=4.5 Hz), 5.34 (1H, s), 5.40 (1H,s), 6.20 (1H, dd, J=8.0, 1.1 Hz), 6.32 (1H, dd, J=8.0, 1.1 Hz), 6.67(1H, t, J=8.0 Hz), 7.20-7.34 (10H, m).

IR (liquid film method) 3514, 3062, 3030, 2928, 2870, 1736, 1620, 1589,1510, 1485, 1454, 1350, 1249, 1207, 1166, 1096, 1073, 1040 cm⁻¹

Mass (EI, m/e) 361 (M⁺)

Reference Example 21

4-(2-(1,1-diphenylethoxy)ethyl)-8-hydroxy-3,4-dihyro-2H-1,4-benzoxazine

8-acetoxy-3,4-(2-(1,1-diphenylethoxy)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine(386 mg) was dissolved in THF (10 ml), and a 1.0M borane THF solution (3ml) was added to the resultant solution at 0° C., followed by stirringat room temperature for 4 hours. After water was added to the reactionsolution to terminate reaction, the reaction solution was extracted withethyl acetate. The resultant organic layer was washed with water, sodiumbicarbonate water, water and saturated brine, dried over sodium sulfate,and then concentrated. The residue was roughly purified bymedium-pressure column chromatography (solvent:ethylacetate/cyclohexane=1/5). The thus-obtained oily substance was dissolvedin THF (1 ml) and methanol (10 ml), and anhydrous potassium carbonate(170 mg) was added to the resultant solution, and the mixture wasstirred at room temperature for 1 hour. The solvent was distilled offunder reduced pressure, and the residue was poured into 5% citric acid,and then extracted with ethyl acetate. The resultant organic layer waswashed with water and saturated brine, dried over sodium sulfate, andconcentrated to obtain the colorless oily object compound (339 mg, yield99%).

¹H-NMR (300 MHz, CDCl₃) δ1.83 (3H, s), 3.40-3.52 (6H, m), 4.25 (2H, t,J=4.5 Hz), 5.38 (1H, s), 6.11 (1H, dd, J=8.1, 1.4 Hz), 6.30 (1H, dd,J=8.1, 1.4 Hz), 6.63 (1H, t, J=8.1 Hz), 7.17-7.36 (10H, m).

IR (KBr method) 3510, 2934, 2874, 1620, 1591, 1512, 1485, 1448, 1348,1251, 1209, 1079, 1062, 1031, 756, 702 cm⁻¹

Mass (EI, m/e) 375 (M⁺)

Reference Example 224-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine

8-acetoxy-4-(4,4-diphenylpentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine(424 mg) was dissolved in THF (10 ml), and a 1.0M borane THF solution (4ml) was added to the resultant solution at 0° C., followed by stirringat room temperature overnight. After water was added to the reactionsolution to terminate reaction, the reaction solution was extracted withethyl acetate. The resultant organic layer was washed with water, sodiumbicarbonate water, water and saturated brine, dried over sodium sulfate,and then concentrated. The thus-obtained oily substance was dissolved inTHF (1 ml) and methanol (10 ml), and anhydrous potassium carbonate (170mg) was added to the resultant solution, and the mixture was stirred atroom temperature for 30 minutes. The solvent was distilled off underreduced pressure, and the residue was poured into 5% citric acid, andthen extracted with ethyl acetate. The resultant organic layer waswashed with water and saturated brine, dried over sodium sulfate, andconcentrated to obtain the colorless oily object compound (391 mg, yield99%).

¹H-NMR (300 MHz, CDCl₃) δ1.36-1.48 (2H, m), 1.63 (3H, s), 2.08-2.16 (2H,m), 3.15 (2H, t, J=7.3 Hz), 3.19 (2H, t, J=4.4 Hz), 4.22 (2H, t, J=4.4Hz), 5.36 (1H, s), 6.10 (1H, dd, J=8.1, 1.1 Hz), 6.31 (1H, dd, J=8.1,1.1 Hz), 6.66 (1H, t, J=8.1 Hz), 7.14-7.21 (6H, m), 7.23-7.29 (4H, m).

IR (KBr method) 3500, 2974, 1618, 1591, 1487, 1446, 1377, 1354, 1303,1249, 1212, 1199, 1164, 1091, 1075, 1044, 1029, 909, 756, 727, 714, 694cm⁻¹

Mass (EI, m/e) 373 (M⁺)

Reference Example 23 N-diphenylmethyl-2-chloroacetamide

A solution of N-diphenylmethylamine (1103 mg) in methylene chloride (20ml) was stirred at 0° C. Triethylamine (1.70 ml) and chloroacetylchloride (0.72 ml) were added to the solution, and the mixture wasstirred at 0° C. for 40 minutes. After water (20 ml) was added to thereaction mixture, the mixture was extracted with ethyl acetate. Theresultant organic layer was washed with saturated brine, dried oversodium sulfate, and concentrated. The residue was purified by silica gelcolumn chromatography (developing solvent:n-hexane/ethyl acetate=5/1) toobtain the object compound (1522 mg, yield 97%).

¹H-NMR (300 MHz, CDCl₃) δ4.13 (2H, s), 6.26 (1H, d, J=8.1 Hz), 7.13-7.40(11H, m).

IR (KBr method) 3204, 3042, 1554, 1495, 1454, 1420, 1237, 1090, 1060,1031, 987, 925, 857, 786, 762, 748, 703 cm⁻¹

Mass (EI, m/e) 259 (M⁺)

Reference Example 24N-diphenylmethyl-2-(8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamide

A solution of8-(tetrahydropyrane-2-yloxy)-3-oxo-3,4-dihydro-2H-1,4-benzooxazine (538mg) in DMF (15 ml) was stirred at 0° C., and t-BuOK (333 mg) was addedto the solution, and the mixture was stirred for 10 minutes. A solutionof N-diphenylmethyl-2-chloroacetamide (841 mg) DMF (5 ml) was then addedto the resultant mixture, and the mixture was stirred at roomtemperature for 160 minutes. After water (25 ml) was added to thereaction mixture, the precipitated solid was filtered off, and thefiltrate was then extracted with ethyl acetate. The resultant organiclayer was washed with saturated brine, dried over sodium sulfate, andconcentrated. The thus-obtained residue and the solid filtered off werecombined, and the combined mixture was suspended in methanol (200 ml).p-Toluenesulfonic acid-hydrate (156 mg) was added to the suspension, andthe mixture was stirred at room temperature for 15 hours. Theprecipitated solid was filtered off, and the filtrate was concentrated.The residue was purified by silica gel column chromatography (developingsolvent:n-hexane/ethyl acetate=2/3) to obtain the object compound (738mg, yield 88%).

¹H-NMR (300 MHz, CDCl₃) δ4.61 (2H, s), 4.72 (2H, s), 5.46 (1H, s), 6.21(1H, d, J=8.1 Hz), 6.67-6.78 (3H, m), 6.93 (1H, t, J=8.3 Hz), 7.10-7.17(4H, m), 7.21-7.33 (6H, m).

IR (KBr method) 3280, 1661, 1543, 1494, 1482, 1421, 1375, 1350, 1236,1176, 1150, 1086, 1043, 977, 956, 823, 769, 750, 724, 700 cm⁻¹

Mass (EI m/e) 388 (M⁺)

Reference Example 253-oxo-4-(2-(benzyloxy)ethyl)-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

Anhydrous DMF (12 ml) was added to sodium hydride (353 mg) to form asuspension, and a solution of3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (2.02g) in anhydrous DMF (15 ml) was added to the resultant suspension at 0°C., and the mixture was stirred at room temperature for 1 hour. Asolution of benzyl-2-bromoethyl ether in anhydrous DMF (5 ml) was addedto the mixture, and the mixture was stirred at room temperature for 21hours. The solvent was distilled off under reduced pressure, and theresidue was then poured into a saturated ammonium chloride aqueoussolution, and then extracted with ethyl acetate. The resultant organiclayer was dried over magnesium sulfate, and concentrated. The residuewas purified by column chromatography (silica gel:hexane/ethylacetate=2/1) to obtain the object compound (1.99 g, yield 65%).

¹H-NMR (300 MHz, CDCl₃) δ1.59-1.75 (3H, m), 1.82-2.08 (3H, m), 3.57-3.64(1H, m), 3.73 (2H, t, J=5.9 Hz), 3.93-4.01 (1H, m), 4.14 (2H, t, J=5.9Hz), 4.53 (2H, s), 4.61 (2H, s), 5.42 (1H, t, J=3.3 Hz), 6.86-6.93 (3H,m), 7.25-7.35 (5H, m).

IR (liquid film method) 3585, 3061, 3031, 2945, 2869, 1736, 1686, 1609,1590, 1481, 1454, 1401, 1358, 1318, 1273, 1204, 1183, 1149, 1115, 1038,952, 917, 873, 818, 770, 737, 698, 672 cm⁻¹

Mass (EI, m/e) 383 (M⁺)

Reference Example 268-hydroxy-3-oxo-4-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine

3-oxo-4-(2-(benzyloxy)ethyl)-8-(tetrahydropyrane-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine(1.89 g) was dissolved in methanol (100 ml), and pyridiniump-toluenesulfonate (126 mg) was added to the resultant solution, and themixture was refluxed for 12 hours. The solvent was distilled off underreduced pressure, and the residue was poured into a saturated sodiumbicarbonate aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by column chromatography (silicagel:hexane/ethyl acetate=1/1) to obtain the object compound (1.18 g,yield 80%).

¹H-NMR (300 MHz, CDCl₃) δ3.73 (2H, t, J=5.9 Hz), 4.14 (2H, t, J=5.9 Hz),4.53 (2H, s), 4.63 (2H, s), 5.61 (1H, s), 6.68-6.76 (2H, m), 6.87-6.92(1H, m), 7.23-7.34 (5H, m).

IR (liquid film method) 3353, 3031, 2866, 1734, 1683, 1612, 1492, 1453,1405, 1373, 1341, 1227, 1173, 1142, 1100, 1044, 1006, 807, 772, 734, 699cm⁻¹

Mass (EI, m/e) 299 (M⁺)

Reference Example 273-oxo-4-(2-(benzyloxy)ethyl)-8-(trifluoromethanesulfonyloxy)-3,4-dihydro-2H-1,4-benzoxazine

8-hydroxy-3-oxo-4-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine(1.10 g) was dissolved in dichloromethane (18 ml), and 2,6-lutidine(0.85 ml) and trifluoromethanesulfonic anhydride (1.50 ml) were added tothe resultant solution, and the mixture was stirred at −78° C. for 1.5hours. The reaction solution was poured into a saturated ammoniumchloride aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by column chromatography (silicagel:hexane/ethyl acetate=2/1) to obtain the object compound (1.40 g,yield 89%).

¹H-NMR (300 MHz, CDCl₃) δ3.76 (2H, t, J=5.6 Hz), 4.14 (2H, t, J=5.6 Hz),4.52 (2H, s), 4.67 (2H, s), 6.94-7.06 (2H, m), 7.21-7.34 (6H, m).

IR (liquid film method) 3033, 2866, 1694, 1615, 1500, 1478, 1425, 1333,1303, 1212, 1168, 1139, 1043, 1001, 900, 850, 830, 798, 779, 758, 734,700, 665, 598 cm⁻¹

Mass (EI, m/e) 431 (M⁺)

Reference Example 28 Methyl(E)-3-(3-oxo-4-(2-(benzyloxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yl)acrylate

3-oxo-4-(2(benzyloxy)ethyl)-8-(trifluoromethanesulfonlyloxy)-3,4-dihydro-2H-1,4-benzoxazine(1.32 g) was dissolved in anhydrous DMF (12 ml), and triethylamine (2.6ml), lithium chloride (388 mg), tris(2-methylphenyl)phosphine (466 mg),palladium acetate (67 mg) and methyl acrylate (0.70 ml) were added tothe resultant solution, and the mixture was stirred at 100° C. for 14hours. The reaction mixture was filtered, and then the residue waswashed with water and a saturated brine, and extracted with ethylacetate. The resultant organic layer was dried over magnesium sulfate,and concentrated. The residue was purified by column chromatography(silica gel:hexane ethyl acetate=2/1) to obtain the object compound(1.09 g, yield 97%).

¹H-NMR (300 MHz, CDCl₃) δ3.75 (2H, t, J=5.6 Hz), 3.82 (3H, s), 4.15 (2H,t, J=5.6 Hz), 4.53 (2H, s), 4.65 (2H, s), 6.53 (1H, d, J=16.2 Hz), 7.01(1H, t, J=8.0 Hz), 7.23-7.33 (7H, m), 7.95 (1H, d, J=16.2 Hz).

IR (liquid film method) 3585, 3031, 2998, 2950, 2864, 1686, 1634, 1585,1482, 1454, 1435, 1402, 1315, 1273, 1172, 1094, 1043, 988, 934, 866,810, 787, 740, 699, 651 cm⁻¹

Mass (EI, m/e) 367 (M⁺)

Reference Example 29 Methyl3-(4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)propionate

10% Pd-C (310 mg) was dissolved in ethanol (10 ml), and deaerated, andthe air in a reactor was replaced by argon. A solution of methyl(E)-3-(3-oxo-4-(2-benzyloxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yl)acrylate(1.04 g) in ethanol (14 ml) was added to the resultant solution. A 0.1Mhydrochloric acid aqueous solution (2 ml) was then added to the mixture,and the mixture was stirred at room temperature for 37 hours in thereactor in which the atmosphere was replaced by hydrogen. The reactionmixture was filtered with Celite, and then the filtrate wasconcentrated. The residue was purified by column chromatography (silicagel:hexane/ethyl acetate=1/3) to obtain the object compound (747 mg,yield 95%).

¹H-NMR (300 MHz, CDCl₃) δ2.61 (2H, t, J=7.7 Hz), 2.96 (2H, t, J=7.7 Hz),3.67 (3H, s), 3.93 (2H, t, J=5.5 Hz), 4.12 (2H, t, J=5.5 Hz), 4.63 (2H,s), 6.90-7.01 (3H, m).

IR (liquid membrane method) 3450, 2952, 2888, 2084, 1736, 1681, 1611,1590, 1481, 1438, 1408, 1370, 1304, 1273, 1227, 1201, 1174, 1129, 1089,1051, 983, 944, 907, 840, 809, 783, 743, 711 cm⁻¹

Mass (EI, m/e) 279 (M⁺)

Reference Example 304-(3-(tert-butyldimethylsilyloxy)propyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

3-oxo-8-(tetrahydropyran-2-yl)-3,4-dihydro-2H-1,4-benzoxazine (2.0 g)was dissolved in DMF (25 ml), and potassium t-butoxide (1.1 g) was addedto the resultant solution, and the mixture was stirred at 0° C. for 15minutes and then at room temperature for 15 minutes. The reactionsolution was cooled to 0° C., and3-(tert-butyldimethylsilyloxy)-1-bromopropane (2.1 ml) was then added tothe reaction solution, and the mixture was stirred for 3 hours at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with a saturated ammonium chloride aqueous solution and saturatedbrine, and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off under reduced pressure, and the resultant residue waspurified by column chromatography (silica gel:ethylacetate/n-hexane=3:17) to obtain the object compound (2.55 g, yield75%).

Pale yellow oily substance

¹H-NMR (300 MHz, CDCl₃) δ0.07 (6H, s), 0.93 (9H, s), 1.60-1.75 (2H, m),1.82-2.12 (6H, m), 3.56-3.65 (1H, m), 3.70 (2H, t, J=5.7 Hz), 3.92-4.06(3H, m), 4.62 (2H, s), 5.42 (1H, t, J=3.0 Hz), 6.83-6.96 (3H, m).

IR (liquid film method) 2951, 2856, 1688, 1610, 1481, 1404, 1358, 1275,1202, 1181, 1145, 1099, 1038, 1022, 950, 918, 835, 776 cm⁻¹

Mass (El, m/e) 421 (M⁺)

Reference Example 314-(3-hydroxypropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

4-(3-(tetra-butyldimethylsilyloxy)propyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine(2.75 g) was dissolved in THF (20 ml), and tetrabutylammonium fluoride(1.0M in THF) was then added to the resultant solution at 0° C.,followed by stirring for 14.5 hours at room temperature. The reactionsolution was diluted with ethyl acetate, washed with saturated brine,and then dried over anhydrous sodium sulfate. Then, the solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by column chromatography (silica gel:ethyl acetate/n-hexane=1:1to 3:1) to obtain the object compound (2.0 g, yield 99.8%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.60-1.77 (2H, m), 1.82-2.12 (6H, m), 2.99 (1H,t, J=6.8 Hz), 3.54-3.65 (3H, m), 3.91-4.02 (1H, m), 4.10 (2H, t, J=6.2Hz), 4.67 (2H, s), 5.43 (1H, t, J=3.0 Hz), 6.76 (1H, dd, J=6.9, 3.0 Hz),6.90-7.00 (2H, m).

IR (liquid film method) 3447, 2946, 1680, 1610, 1481, 1409, 1356, 1270,1180, 1143, 1119, 1037, 957, 908, 872, 817, 754 cm⁻¹

Mass (EI, m/e) 307 (M⁺)

Reference Example 324-(3-azidopropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

4-(3-hydroxypropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine(2.0 g) was dissolved in dichloromethane (20 ml), and triethylamine(1.27 ml) and a methanesulfonyl chloride (0.6 ml) were added to theresultant solution at 0° C., followed by stirring for 2 hours. Thereaction solution was diluted with chloroform, washed with saturatedbrine, and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off under reduced pressure to obtain a crude mesylcompound. The crude mesyl compound was dissolved in DMF (20 ml), andsodium azide (510 mg) was added to the resultant solution, and themixture was stirred at room temperature for 15 hours. The reactionsolution was diluted with ethyl acetate, washed with saturated brine,and then dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure, and the resultant residue was purified bycolumn chromatography (silica gel: ethyl acetate/n-hexane=1:9) to obtainthe object compound (2.07 g, yield 96%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.60-1.76 (2H, m), 1.82-2.09 (6H, m), 3.42 (2H,t, J=6.5 Hz), 3.57-3.66 (1H, m), 3.92-4.06 (3H, m), 4.63 (2H, s), 5.43(1H, t, J=3.2 Hz), 6.70 (1H, dd, J=7.8, 1.8 Hz), 6.89-7.01 (2H, m).

IR (liquid film method) 2946, 2874, 2098, 1686, 1609, 1481, 1404, 1355,1271, 1200, 1180, 1145, 1119, 1075, 1036, 953, 921, 872, 817, 755 cm⁻¹

Mass (EI, m/e) 332 (M⁺)

Reference Example 334-(3-(2-naphthoylamino)propyl)-3-oxo-8-(tetrahydropyrane-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine

A solution of4-(3-azidopropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine(1.0 g) in ethanol (10 ml) was added to a suspension of 10% palladiumcarbon (containing 50% water) (100 mg) in ethanol (20 ml), and themixture was stirred at room temperature for 22 hours under a hydrogenatmosphere. The reaction solution was filtered with Celite, and thesolvent was distilled off under reduced pressure to obtain a crudeamine. The thus-obtained crude amine was dissolved in DMF (10 ml), and2-naphthalenecarboxylic acid (780 mg) and1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (865 mg)were added to the resultant solution, and the mixture was stirred atroom temperature for 19 hours. The reaction solution was diluted withethyl acetate, washed with saturated brine, and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the resultant residue was purified by columnchromatography (silica gel:ethyl acetate/n-hexane=3:2) to obtain theobject compound (717 mg, yield 55%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.55-2.13 (8H, m), 3.50 (2H, dd, J=12.0, 6.3Hz), 3.57-3.67 (1H, m), 3.90-4.02 (1H, m), 4.08-4.17 (2H, m), 4.71 (2H,s), 5.43 (1H, t, J=3.3 Hz), 6.75 (1H, dd, J=7.1, 2.6 Hz), 6.92-7.02 (2H,m), 7.50-7.64 (3H, m), 7.84-8.01 (4H, m), 8.44 (1H, s).

IR (liquid film method) 2943, 1684, 1636, 1534, 1480, 1411, 1291, 1186,1147, 1021, 958, 819, 772, 483 cm⁻¹

Mass (EI, m/e) 460 (M⁺)

Reference Example 344-(3-(2-naphthylmethylamino)propyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine

4-(3-(2-naphthoylamino)propyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzooxazine(398 mg) was dissolved in methanol (5 ml), and a 1N hydrochloric acidaqueous solution was added to the resultant solution, and the mixturewas stirred at 0° C. for 1 hour. The reaction solution was extractedwith ethyl acetate, and the resultant organic layer was washed withsaturated brine, and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultantresidue was dissolved in THF (5 ml). A borane THF complex (1.0 M in THF,2.8 ml) was added to the resultant solution, and then the mixture wasrefluxed under heating for 3.5 hours. A saturated sodium bicarbonateaqueous solution was added to the reaction solution, and the mixture wasthen extracted with ethyl acetate. The resultant organic layer waswashed with saturated brine, and then the solvent was distilled offunder reduced pressure. The resultant residue was purified by columnchromatography (silica gel:ethyl acetate/n-hexane=3:7) to obtain theobject compound (166 mg, yield 52%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.76-1.91 (1H, m), 2.16-2.33 (1H, m), 2.70-2.83(1H, m), 2.85-2.97 (1H, m), 3.00-3.11 (2H, m), 3.13-3.24 (1H, m), 3.31(1H, dd, J=12.1, 4.9, 2.7 Hz), 3.70 (1H, dd, J=13.5, 9.1 Hz), 4.00-4.17(2H, m), 4.31 (1H, dd, J=13.5, 3.6 Hz), 4.53 (1H, br. s), 5.42 (1H, s),6.01 (1H, dd, J=8.2, 1.4 Hz), 6.43 (1H, dd, J=8.2, 1.4 Hz), 6.57 (1H, t,J=8.2 Hz), 7.17 (1H, dd, J=8.2, 1.9 Hz), 7.46-7.56 (2H, m), 7.58 (1H,br. s), 7.66-7.75 (2H, m), 7.80-7.87 (1H, m).

IR (liquid film method) 3518, 2945, 1617, 1509, 1482, 1350, 1166, 1074,1042, 909, 859, 821, 759, 731 cm⁻¹

Mass (EI, m/e) 348 (M⁺)

Reference Example 35 6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine

5-hydroxy-1-tetralone (506 mg) was dissolved in trifluoroacetic acid (10ml) in a 50-ml short-neck flask with a condenser in an argon atmosphere,followed by stirring at room temperature. Sodium azide (254 mg) wasadded to the resultant solution, and the mixture was refluxed underheating. Since the progress of reaction stopped, the reaction solutionwas poured into water (20 ml), neutralized with a sodium bicarbonateaqueous solution, and then extracted with ethyl acetate. The combinedorganic layers were washed with saturated brine, dried over anhydroussodium sulfate, and then concentrated to obtain a residue. Thethus-obtained residue was dissolved in methylene chloride (5 ml) andpyridine (2 ml) in a 100-ml short-neck flask, and the resultant solutionwas stirred at room temperature. Acetic anhydride (0.45 ml) was added tothe resultant solution, and the mixture was stirred at room temperature.After disappearance of the raw materials was confirmed, the reactionsolution was added to a saturated ammonium chloride aqueous solution (30ml), and then extracted with ethyl acetate. The resultant organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and then concentrated. The resultant residue was purified by columnchromatography (silica gel:hexane/ethyl acetate=1/1) to obtain theobject compound (416 mg, yield a 61%).

¹H-NMR (300 MHz, CDCl₃) δ1.99-2.07 (2H, m), 2.14 (2H, t, J=6.9 Hz), 2.32(3H, s), 2.56 (2H, t, J=7.2 Hz), 6.89 (2H, d, J=8.1 Hz), 7.24 (1H, t,J=8.1 Hz), 9.66 (1H, s).

IR (KBr method) 3188, 1758, 1676, 1642, 1580, 1473, 1381, 1220, 1176,1067, 1021, 777 cm⁻¹

Mass (EI, m/e) 219 (M⁺)

Reference Example 36 Methyl(6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate

6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine (252 mg) wasdissolved in DMF (5 ml), and the resultant solution was stirred at roomtemperature. Potassium carbonate (509 mg) and methyl bromoacetate (0.22ml) were added to the solution at room temperature. After disappearanceof the raw materials was confirmed, water (20 ml) was added to thereaction solution, and the mixture was then extracted with ethylacetate. The resultant organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and then concentrated. Theresultant residue was purified by column chromatography (silicagel:hexane/ethyl acetate=1/1) to obtain the object compound ml (333 mg,yield 99%).

¹H-NMR (300 MHz, CDCl₃) δ1.95-2.30 (2H, m), 2.30-2.41 (2H, m), 2.35 (3H,s), 2.78-2.90 (2H, m), 3.75 (3H, s), 4.51 (2H, s), 6.96 (1H, dd, J=8.1,0.9 Hz), 7.06 (1H, dd, J=8.1, 0.9 Hz), 7.27 (1H, t, J=8.1 Hz).

IR (liquid film method) 2958, 1750, 1661, 1607, 1586, 1437, 1412, 1379,1172, 1110, 1083, 1015, 980, 920, 731 cm⁻¹

Mass (EI, m/e) 291 (M⁺)

Reference Example 371-(2-hydroxyethyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine

Methyl (6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate(1080 mg) was dissolved in THF (15 ml) under an argon atmosphere, andthe resultant solution was stirred at 0° C. Lithium aluminum hydride(355 mg) was added to the solution, and the mixture was stirred at 0° C.After disappearance of the raw materials was confirmed, the reactionsolution was added to water (100 ml), and then extracted with ethylacetate. The resultant organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and then concentrated. Theresultant residue was purified by column chromatography (silicagel:hexane/ethyl acetate=2/1) to obtain the object compound (624 mg,yield 81%).

¹H-NMR (300 MHz, CDCl₃) δ1.55-1.66 (2H, m), 1.68-1.81 (2H, m), 2.63 (1H,br s), 2.82-2.90 (2H, m), 2.90-2.97 (2H, m), 3.31 (2H, t, J=5.3 Hz),3.71 (2H, t, J=5.3 Hz), 5.31 (1H, br s), 6.47 (1H, dd, J=8.1, 1.2 Hz),6.57 (1H, d, J=8.1 Hz), 6.98 (1H, t, J=8.1 Hz).

IR (liquid film method) 2926, 2850, 1605, 1582, 1495, 1468, 1305, 1257,1230, 1141, 1029, 1004, 785, 733 cm⁻¹

Mass (EI, m/e) 207 (M⁺)

Reference Example 38 Methyl(1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetate

1-(2-hydroxyethyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (52 mg)was dissolved in DMF (3 ml), and the resultant solution was stirred atroom temperature. Potassium carbonate (122 mg) and methyl bromoacetate(0.035 ml) were added to the solution, and the mixture was stirred atroom temperature. After disappearance of the raw materials wasconfirmed, water (20 ml) was added to the reaction solution, and themixture was then extracted with ethyl acetate. The resultant organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and then concentrated. The resultant residue was purified bycolumn chromatography (silica gel:hexane/ethyl acetate=2/1) to obtainthe object compound (47 mg, yield 67%).

¹H-NMR (300 MHz, CDCl₃) δ1.55-1.67 (2H, m), 1.68-1.80 (2H; m), 2.51 (1H,br s), 2.93-2.98 (4H, m), 3.31 (2H, t, J=5.1 Hz), 3.69 (2H, t, J=5.1Hz), 3.80 (3H, s), 4.62 (2H, s), 6.46 (1H, dd, J=8.1, 0.9 Hz), 6.67 (1H,dd, J=8.1, 0.9 Hz), 7.06 (1H, t, J=8.1 Hz).

IR (liquid film method) 2928, 2858, 1760, 1599, 1580, 1470, 3:441, 1290,1212, 1181, 1145, 1125, 1098, 1046, 733 cm⁻¹

Mass (EI, m/e) 279 (M⁺)

Reference Example 39 5-(t-butyldimethylsiloxy)quinoline

5-hydroxyquinoline (101 mg) was dissolved in DMF (5 ml) under an argonatmosphere, and the resultant solution was stirred at room temperature.Imidazole (113 mg) and t-butyldimethylsilyl chloride (162 mg) were addedto the solution, and the mixture was stirred at room temperature. Afterdisappearance of the raw materials was confirmed, water (5 ml) was addedto the reaction solution, and the mixture was then extracted with ethylacetate. The resultant organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and then concentrated. Theresultant residue was purified by column chromatography (silicagel:hexane/ethyl acetate=9/1) to obtain the object compound (197 mg,yield 100%).

¹H-NMR (300 MHz, CDCl₃) δ0.30 (6H, s), 1.09 (9H, s), 6.92 (1H, dd,J=7.8, 0.9 Hz), 7.38 (1H, dd, J=8.7, 4.5 Hz), 7.56 (1H, dd, J=8.4, 7.5Hz), 7.73 (1H, dt, J=8.4, 0.9 Hz), 8.50 (1H, ddd, J=8.7, 2.1, 0.9 Hz),8.89 (1H, dd, J=4.5, 1.8 Hz).

IR (liquid film method) 2934, 2862, 1593, 1574, 1470, 1396, 1365, 1317,1261, 1201, 1164, 1141, 1087, 1056, 1019, 919, 833, 797 cm⁻¹

Mass (EI, m/e) 259 (M⁺)

Reference Example 405-(t-butyldimethylsiloxy)-1,2,3,4-tetrahydroquinoline

5-(t-butyldimethylsiloxy)quinoline (1715 mg) was dissolved in ethanol(50 ml), and the air in a reactor was substituted by argon. 10% Pd—C(100 mg) was added to the resultant solution, and the mixture wasstirred at room temperature in the reactor in which the atmosphere wasreplaced by hydrogen. After disappearance of the raw materials wasconfirmed, the solid was filtered off, and the filtrate wasconcentrated. The resultant residue was purified by columnchromatography (silica gel:hexane/ethyl acetate=10/1) to obtain theobject compound (1426 mg, yield 82%).

¹H-NMR (300 MHz, CDCl₃) δ0.22 (6H, d, J=0.6 Hz), 1.00 (9H, d, J=0.6 Hz),1.86-1.97 (2H, m), 2.65 (2H, t, J=6.6 Hz), 3.21-3.56 (2H, m), 3.80 (1H,br s), 6.13 (1H, d, J=8.1 Hz), 6.14 (1H, d, J=8.1 Hz), 6.82 (1H, td,J=7.8, 0.6 Hz).

IR (liquid film method) 2932, 2860, 1601, 1495, 1473, 1448, 1348, 1307,1286, 1241, 1187, 1118, 1094, 1048, 1000, 934, 880, 841, 781 cm⁻¹

Mass (EI, m/e) 263 (M⁺)

Reference Example 41 Methyl3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetate

7-hydroxy-3-(2-hydroxyethyl)benzofuran (7.01 g) was dissolved indimethylformamide (100 ml), and potassium carbonate (5.76 g) and methylbromoacetate (4.74 ml) were added to the resultant solution, and themixture was stirred at room temperature for 21 hours. The reactionsolution was filtered with Celite, and the filtrate was concentrated.Ethyl acetate (300 ml) was added to the residue, and then the mixturewas washed with water and saturated brine, and dried over sodiumsulfate. After sodium sulfate was filtered off, the filtrate wasconcentrated, and the residue was dissolved in methanol (100 ml). 5%Pd/C (1.0 g), and acetic acid (5 ml) were added to the resultantsolution, and the mixture was stirred at room temperature for 23 hoursunder a hydrogen atmosphere. The reaction solution was filtered withCelite, and the filtrate was concentrated. Ethyl acetate (300 ml) wasadded to the residue, and the mixture was washed with water andsaturated brine, and dried over sodium sulfate. After sodium sulfate wasfiltered off, the filtrate was concentrated, and the residue waspurified by flash column chromatography using silica gel (elutionsolvent:hexane/ethyl acetate=1/2) to obtain the object compound (7.80 g,yield 74%).

¹H-NMR (300 MHz, CDCl₃) δ1.37 (1H, t, J=4.9 Hz), 1.79-1.91 (1H, m),2.11-2.00 (1H, m), 3.57-3.67 (1H, m), 3.77 (2H, dt, J=4.9, 6.3 Hz), 3.80(3H, s), 4.34 (1H, dd, J=6.6, 8.8 Hz), 4.73 (2H, s), 4.74 (1H, t, J=8.8Hz), 6.71-6.74 (1H, m), 6.80 (1H, t, J=8.0 Hz), 6.86-6.89 (1H, m).

Mass (EI, m/e) 252 (M⁺)

Reference Example 423-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid

Methyl 3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetate (7.80 g)was dissolved in methanol (100 ml), and a 2N sodium hydroxide aqueoussolution (20 ml) was added to the resultant solution, and the mixturewas stirred at room temperature for 4 hours. 1N hydrochloric acid (45ml) was added to the reaction solution, and the mixture wasconcentrated. The residue was dissolved in ethyl acetate (200 ml),washed with water and saturated brine, and then dried over sodiumsulfate. After sodium sulfate was filtered off, the filtrate wasconcentrated, and the residue was recrystallized from ethylacetate/n-hexane to obtain the object compound (6.21 g, yield 84%).

mp. 91-93° C. (recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CD₃OD) δ1.70-1.82 (1H, m), 1.94-2.05 (1H, m), 3.51-3.61(1, m), 3.66 (2H, dt, J=2.5, 6.6 Hz), 4.28 (1H, dd, J=6.6, 8.8 Hz), 4.68(1H, t, J=8.8 Hz), 4.69 (2H, s), 6.76-6.89 (3H, m).

Reference Example 43(+)-3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid(−)-cis-2-benzylaminocyclohexanemethanol salt

3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid (2.91 g) wasdissolved in ethanol (30 ml), and(−)-cis-2-benzylaminocyclohexanemethanol (1.88 g) was added to theresultant solution, followed by reflux and dissolution. Ethyl acetate(15 ml) was then added to the resultant solution, and the mixture wascooled to room temperature to obtain crystals. The thus-obtainedcrystals were filtered off, and then recrystallized 6 times from ethanolto obtain the object compound of 97%e.e (0.77 g, yield 14%).

Reference Example 44 Methyl(+)-3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetate

(+)-3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid(−)-cis-2-benzylaminocyclohexanemethanol salt (580 mg) was dissolved inwater (30 ml), and the resultant solution was rendered acidic with 1Nhydrochloric acid, and then extracted with ethyl acetate twice. Thecombined organic layers were washed with saturated brine, and dried oversodium sulfate. Sodium sulfate was filtered off, and the filtrate wasconcentrated. The residue was dissolved in 5 ml of methanol, and 2 dropsof conc. hydrochloric acid were added to the resultant solution,followed by reflux for 30 minutes. After the reaction solution wascooled to room temperature, the solvent was distilled off under reducedpressure, and the residue was purified by flash column chromatographyusing silica gel (elution solvent:hexane/ethyl acetate=1/2) to obtainthe object compound (274 mg, yield 86%). [α]_(D) 28=+18.20 (c=0.455,CHCl₃)

Reference Example 455-(t-butyldimethylsiloxy)-1-chloroacetyl-1,2,3,4-tetrahydroquinoline

5-(t-butyldimethylsiloxy)-1,2,3,4-tetrahydroquinoline (1426 mg) wasdissolved in methylene chloride (50 ml) under an argon atmosphere, andthe resultant solution was stirred at 0° C. Pyridine (1.00 ml) andchloroacetyl chloride (0.70 ml) were added to the solution, and themixture was stirred at 0° C. After disappearance of the raw materialswas confirmed, the reaction solution was added to water (50 ml), andthen extracted with ethyl acetate. The resultant organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated. The resultant residue was purified by columnchromatography (silica gel:hexane/ethyl acetate=5/1) to obtain theobject compound (1839 mg, yield 100%).

¹H-NMR (300 MHz, CDCl₃) δ0.24 (6H, s), 1.02 (9H, s), 1.98 (1H, quint,J=6.6 Hz), 2.70 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=6.6 Hz), 4.25 (2H, s),6.68 (1H, d, J=8.4 Hz), 6.75-7.00 (1H, m), 7.08 (1H, t, J=8.0 Hz).

IR (liquid film method) 2958, 2862, 1667, 1584, 1470, 1388, 1340, 1261,1205, 1180, 1147, 1114, 1006, 942, 839, 828, 814, 783 cm⁻¹

Mass (EI, m/e) 339 (M³⁰)

Reference Example 461-((1,1-diphenylethylthio)acetyl)-5-hydroxy-1,2,3,4-tetrahydroquinoline

1,1-diphenylethanethiol (203 mg) was dissolved in DMF (3 ml) under anargon atmosphere, and the resultant solution was stirred at 0° C. Sodiumhydride (65 mg) was added to the solution, and the mixture was stirredat 0° C. for 10 minutes. A solution of5-(t-butyldimethylsiloxy)-1-chloroacetyl-1,2,3,4-tetrahydroquinoline(252 mg) in DMF (3 ml) was then added to the mixture, and the mixturewas stirred at room temperature. After disappearance of the rawmaterials was confirmed, the reaction solution was added to water (30ml), and then extracted with ethyl acetate. The resultant organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated. The resultant residue was purified by columnchromatography (silica gel:hexane/ethyl acetate=2/1) to obtain theobject compound (294 mg, yield 98%).

¹H-NMR (300 MHz, CDCl₃) δ1.88-1.98 (2H, m), 2.05 (3H, s), 0 2.65 (2H, t,J=7.1 Hz), 3.25 (2H, s), 3.50-3.80 (2H, m), 4.96 (1H, br s), 6.50-6.80(1H, m), 6.60 (1H, d, J=8.7 Hz), 6.94 (1H, t, J=8.1 Hz), 7.14-7.40 (10H,m).

IR (KBr method) 2930, 1622, 1586, 1493, 1470, 1408, 1338, 1311, 1288,1201; 1147, 1069, 915, 698 cm⁻¹

Mass (El, m/e) 403 (M³⁰)

Reference Example 471-(2-(1,1-diphenylethylthio)ethyl)-5-hydroxy-1,2,3,4-tetrahydroquinoline

1-((1,1-diphenylethylthio)acetyl)-5-hydroxy-1,2,3,4-tetrahydroquinoline(136 mg) was dissolved in THF (5 ml), and the resultant solution wasstirred at 0° C. A borane THF complex (1.0N in THF) (2.0 ml) was addedto the solution, and the mixture was stirred at room temperature. Afterdisappearance of the raw materials was confirmed, the reaction solutionwas added to a saturated ammonium chloride aqueous solution (20 ml), andthen extracted with ethyl acetate. The resultant organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, and aconcentrated. The resultant residue was purified by columnchromatography (silica gel:hexane/ethyl acetate=5/1) to obtain theobject compound (60 mg, yield 46%).

¹H-NMR (300 MHz, CDCl₃) δ1.82-1.92 (2H, m), 2.07 (3H, s), 2.48-2.64 (4H,m), 3.04-3.19 (4H, m), 4.54 (1H, br s), 5.83 (1H d, J=8.1 Hz), 6.07 (1H,dd, J=8.1, 0.9 Hz), 6.81 (1H, t, J=8.1 Hz), 7.20-7.35 (6H, m), 7.39-7.45(4H, m).

IR (liquid film method) 2934, 1615, 1578, 1506, 1481, 1464, 1446, 1332,1270, 1224, 1195, 1152, 1102, 1029, 913, 762, 700 cm⁻¹

Mass (EI, m/e) 389 (M⁺)

Example 1 Methyl(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

Methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(347 mg) was dissolved in methylene chloride (8.0 ml), and triethylamine(0.60 ml) was added to the resultant solution and then cooled to 0° C.Methanesulfonyl chloride (0.08 ml) was added to the mixture, and themixture was stirred at 0° C. for 40 minutes. Methanesulfonyl chloride(0.10 ml) was further added to the mixture, and the mixture was stirredat 0° C. for 1 hour. The reaction solution was poured into a 5% citricacid aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was washed with water, saturated sodiumbicarbonate water, water and saturated brine, dried over magnesiumsulfate, and then concentrated to obtain a mesyl compound.

Sodium hydride (68 mg) was washed with n-hexane, dried under reducedpressure, and then the air was substituted by argon. A solution ofdiphenylmethanethiol (440 mg) in anhydrous DMF (3.5 ml) was added to thesodium hydride at 0° C., and the mixture was stirred at room temperaturefor 10 minutes. A solution of the above mesyl compound in anhydrous DMF(6.0 ml) was added to the mixture, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distilled off under reducedpressure, and the residue was poured into a 5% citric acid aqueoussolution, and then extracted with ethyl acetate. The resultant organiclayer was washed with water and saturated brine, dried over magnesiumsulfate, and concentrated. The resultant residue was purified by columnchromatography (neutral alumina:methyl acetate/n-hexane=1:3) to obtainthe object compound (476 mg, yield 81%). Colorless plate crystal: mp.94-95° C. (recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.61 (2H, m), 3.26 (2H, m), 3.36 (2H, m), 3.78(3H, s), 4.24 (2H, m), 4.65 (2H, s), 5.24 (1H, s), 6.06 (1H, dd, J=1, 8Hz), 6.20 (1H, dd, J=l, 8 Hz), 6.61 (1H, t, J=8 Hz), 7.26-7.31 (6H, m),7.41-7.46 (4H, m).

IR (KBr method) 2954, 1763, 1611, 1489, 1452, 1350, 1245, 1212, 1180,1164, 1129, 1079, 1048, 752, 704 cm⁻¹

Mass (EI, m/e) 449 (M⁺)

Example 2 Methyl(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (1.27g) and 1,1-diphenylethanethiol-(1.13 g) were used to obtain the objectcompound (1.78 g, yield 81%). Colorless columnar crystal: mp. 101° C.(recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.06 (3H, s), 2.51 (2H, t, J=8 Hz), 3.13 (2H,t, J=8 Hz), 3.19 (2H, t, J=4.5 Hz), 3.78 (3H, s), 4.22 (2H, t, J=4.5Hz), 4.65 (2H, s), 6.01 (1H, dd, J=1, 8 Hz), 6.19 (1H, dd, J=1, 8 Hz),6.62 (1H, t, J=8 Hz), 7.21-7.44 (10H, m).

IR (KBr method) 3034, 2930, 2875, 1765, 1611, 1580, 1487, 1444, 1350,1286, 1245, 1212, 1180, 1164, 1129, 760, 700, 681 cm⁻¹

Mass (EI, m/e) 463(M⁺)

Example 3 Methyl(4-(2-(1,1-diphenyl-2,2,2-trifluoroethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (375mg) and 1,1-diphenyl-2,2,2-trifluoroethanethiol (385 mg). were used toobtain the object compound (614 mg, yield 85%).

Pale yellow oily substance

¹H-NMR (300 MHz, CDCl₃) δ2.55 (2H, t, J=7 Hz), 3.17 (4H, m), 3.78 (3H,s), 4.21 (2H, , 4.64 (2H, s), 5.94 (1H, dd, J=1, 8 Hz), 6.19 (1H, dd,J=1, 8 Hz), 6.60 (1H, t, J=8 Hz), 7.31-7.36 (6H, m), 7.42-7.46 (4H, m).

IR (liquid film method) 2934, 1765, 1611, 1580, 1487, 1448, 1350, 1251,1212, 1160, 754, 719, 700 cm⁻¹

Mass (EI, m/e) 517 (M⁺)

Example 4 Methyl(4-(2-(1,1-bis-(4-fluorophenyl)ethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200mg) and 1,1-bis-(4-fluorophenyl)ethanethiol (450 mg) were used to obtainthe colorless oily object compound (311 mg, yield 83%).

¹H-NMR (300 MHz, CDCl₃) δ2.02 (3H, s), 2.50 (2H, t, J=7.6 Hz), 3.21-3.35(6H, m), 3.79 (3H, s), 4.24 (2H, t, J=4.4 Hz), 4.66 (2H, s), 6.22 (1H,d, J=8.5 Hz), 6.27 (1H, d, J=8.5 Hz), 6.70 (1H, t, J=8.5 Hz), 7.17-7.32(10H, m).

IR (liquid film method) 2956, 2932, 1763, 1605, 1578, 1487, 1460, 1439,1377, .1350, 1328, 1288, 1214, 1162, 1133, 1077, 1062, 1013 cm⁻¹

Mass (EI, m/e) 499 (M⁺)

Example 5 Methyl(4-(2-1-methyl-1-phenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (343mg) and 2-phenylpropane-2-thiol (404 mg) were used to obtain the objectcompound (483 mg, yield 94%).

Pale yellow oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.72 (6H, s), 2.42 (2H, t, J=8 Hz), 3.09 (2H,t, J=8 Hz), 3.17 (2H, t, J=4.5 Hz), 3.78 (3H, s), 4.20 (2H, t, J=4.5Hz), 4.64 (2H, s), 5.94(1H, dd, J=1, 8 Hz), 6.17 (1H, dd, J=1, 8 Hz),6.60 (1H, t, J=8 Hz), 7.24 (1H, m), 7.34 (2H, m), 7.54 (2H, m).

IR (liquid film method) 2970, 2928, 2874, 1765, 1611, 1497, 1487, 1448,1348, 1286, 1245, 1212, 1180, 1164, 1129, 1100, 1077, 768, 700 cm⁻¹

Mass (EI, m/e) 401 (M³⁰)

Example 6 Methyl(4-(2-(2,2-diphenylpropylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200mg) and 2,2-diphenylpropanethiol (410 mg) were used to obtain thecolorless oily object compound (134 mg, yield 37%).

¹H-NMR (300 MHz, CDCl₃) δ1.78 (3H, s), 2.36 (2H, t, J=7.6 Hz), 3.24-3.35(6H, m), 3.79 (3H, s), 4.24 (2H, t, J=4.4 Hz), 4.66 (2H, s), 6.22(1H, d,J=8.5 Hz), 6.27 (1H, d, J=8.5 Hz), 6.70 (1H, t, J=8.5 Hz), 7.17-7.32(10H, m).

IR (liquid film method) 3058, 2928, 2880, 1765, 1736, 1609, 1578, 1489,1446, 1375 cm⁻¹

Mass (EI, m/e) 477 (M⁺)

Example 7 Methyl(4-(2-(1,1-bis-(3-thienyl)ethylthio)ethyl-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (150mg) and 1,1-bis-(3-thienyl)ethanethiol (320 mg) were used to obtain thecolorless oily object compound (253 mg, yield 95%).

¹H-NMR (300 MHz, CDCl₃) δ2.05 (3H, s), 2.51-2.58 (2H, m), 3.16 (2H, t,J=7.7 Hz), 3.23 (2H, t, J=4.4 Hz), 3.79 (3H, s), 4.23 (2H, t, J=4.4 Hz),4.65 (2H, s), 6.07(1H, dd, J=8.2, 1.1 Hz), 6.20 (1H, dd, J=8.2, 1.1 Hz),6.66 (1H, t, J=8.2 Hz), 7.11 (2H, dd, J=3.0, 1.4 Hz), 7.14 (2H, dd,J=5.2, 1.4 Hz), 7.29 (2H, dd, J=5.2, 3.0 Hz).

IR (liquid film method) 3108, 2954, 2930, 2878, 1767, 1740, 1615, 1580,1506, 1456, 1375, 1350, 1330, 1288, 1247, 1212, 1164, 1131, 1079, 1050,1004, 928, 777 cm⁻¹

Mass (EI, m/e) 475 (M⁺)

Example 8 Methyl(4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

4-(2-(diphenylmethoxy)-ethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine(161 mg) was dissolved in anhydrous DMF (4 ml), and anhydrous potassiumcarbonate (54 mg) and methyl bromoacetate (0.04 ml) were added to theresultant solution, and the mixture was stirred at room temperatureovernight. The reaction solution was poured into a saturated ammoniumchloride aqueous solution, and then extracted with ethyl acetatecontaining 15% n-hexane. The resultant organic layer was washed withwater and saturated brine, dried over sodium sulfate, and concentrated.The resultant residue was purified by medium-pressure columnchromatography (solvent:ethyl acetate:cyclohexane=1/3) to obtain thecolorless oily object compound (118 mg, yield 97%).

¹H-NMR (300 MHz, CDCl₃) δ3.46 (2H, t, J=4.4 Hz), 3.53 (2H, t, J=5.6 Hz),3.65 (2H, t, J=5.6 Hz), 3.79 (3H, s), 4.26 (2H, t, J=4.4 Hz), 4.68 (2H,s), 5.34 (1H, s), 6.21 (1H, dd, J=8.2, 1.4 Hz), 6.36 (1H, dd, J=8.2, 1.4Hz), 6.68 (1H, t, J=8.2 Hz), 7.19-7.32 (10H, m).

IR (liquid film method) 3064, 3030, 2954, 2870, 1763, 1736, 1611, 1578,1489, 1456, 1350, 1330, 1284, 1212, 1187, 1151, 1093 cm⁻¹

Mass (EI, m/e) 433 (M⁺)

Example 9 Methyl(4-(2-(1,1-diphenylethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 8 was repeated except that4-(2-(1,1-diphenylethoxy)ethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine(239 mg) was used to obtain the colorless oily object compound (229 mg,yield 80%).

¹H-NMR (300 MHz, CDCl₃) δ1.83 (3H, s), 3.40-3.51 (6H, m), 3.79 (3H, s),4.27 (2H, t, J=4.4 Hz), 4.67 (2H, s), 6.19(1H, dd, J=8.2, 1.1 Hz), 6.27(1H, dd, J=8.2, 1.1 Hz), 6.64 (1H, t, J=8.2 Hz), 7.17-7.34 (10H, m).

IR (liquid film method) 2980, 2954, 2874, 1763, 1743, 1613, 1578, 1489,1448, 1350, 1212, 1093 cm⁻¹

Mass (EI, m/e) 447 (M⁺)

Example 10 Methyl(4-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

4-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazinewas dissolved in anhydrous DMF (15 ml), and anhydrous potassiumcarbonate (180 mg) and methyl bromoacetate (0.15 ml) were added to theresultant solution, and the mixture was stirred at room temperatureovernight. The reaction solution was poured into a saturated ammoniumchloride aqueous solution, and then extracted with ethyl acetatecontaining 15% n-hexane. The resultant organic layer was washed withwater and saturated brine, dried over sodium sulfate, and concentrated.The resultant residue was purified by medium-pressure columnchromatography (solvent:ethyl acetate/cyclohexane=1/3) to obtain thecolorless oily object compound (386 mg, yield 92%).

¹H-NMR (300 MHz, CDCl₃) δ1.35-1.47 (2H, m), 1.63 (3H, s), 2.08-2.16 (2H,m), 3.15 (2H, t, J=7.4 Hz), 3.19 (2H, t, J=4.4 Hz), 3.79 (3H, s), 4.24(2H, t, J=4.4 Hz), 4.66 (2H, s), 6.19 (1H, dd, J=8.2, 1.4 Hz), 6.24 (1H,dd, J=8.2, 1.4 Hz), 6.66 (1H, t, J=8.2 Hz), 7.14-7.21 (6H, m), 7.23-7.30(4H, m).

IR (liquid film method) 3060, 3030, 2954, 2876, 1763, 1740, 1613, 1578,1485, 1460, 1444, 1375, 1350, 1328, 1288, 1245, 1210, 1174, 1135, 1108,911 cm⁻¹

Mass (EI, m/e) 445 (M³⁰)

Example 11 Methyl(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

The same process as Example 1 was repeated except that methyl(4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(187 mg) and 1,1-diphenylethanethiol (270 ml) were used to obtain theobject compound (172.5 mg, yield 42%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ2.08 (3H, s), 2.57 (2H, m), 3.79 (3H, s), 3.81(2H, m), 4.59 (2H, s), 4.69 (2H, s), 6.13(1H, dd, J=1, 8 Hz), 6.56 (1H,dd, J=1, 8 Hz), 6.81 (1H, t, J=8 Hz), 7.21-7.34 (6H, m), 7.40-7.45 (4H,m).

IR (liquid film method) 2920, 2332, 1763, 1686, 1611, 1485, 1444, 1402,1317, 1282, 1214, 1195, 1151, 1058, 766, 733, 698, 667 cm⁻¹

Mass (EI, m/e) 477 (M⁺)

Example 12 Methyl(4-((diphenylmethylcarbamoyl)methyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

N-diphenylmethyl-2-(8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamide(735 mg) was dissolved in DMF (30 ml), and the resultant solution wasstirred at room temperature. Potassium carbonate (785 mg) and methylbromoacetate (0.35 ml) were added to the solution, and the mixture wasstirred at room temperature for 18 hours. Water (25 ml) was added to thereaction solution, and the mixture was then extracted with ethylacetate. The resultant organic layer was washed with saturated saline,dried over sodium sulfate, and concentrated. The resultant residue wasrecrystallized from ethyl acetate/n-hexane to obtain the object compound(492 mg, yield 56%)

mp. 183.0-184.0° C.

¹H-NMR (300 MHz, CDCl₃) δ3.80 (3H, s), 4.60 (2H, s), 4.72 (4H, s), 6.21(1H, d, J=6.0 Hz), 6.65 (1H, dd, J=1.5, 8.1 Hz), 6.82 (1H, d, J=7.5 Hz),6.87 (1H, dd; J=1.5, 8 Hz), 6.95 (1H, t, J=8.3 Hz), 7.10-7.17 (4H, m),7.20-7.33 (6H, m).

IR (KBr method) 3301, 1752, 1693, 1662, 1612, 1541, 1484, 1401, 1282,1228, 1192, 1161, 1106, 1056, 862, 767, 700 cm⁻¹

Mass (EI, m/e) 460 (M⁺)

Example 13 Methyl3-(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)propionate

Methyl3-(4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)propionate(300 mg) was dissolved in dichloromethane (5 ml), and triethylamine (0.3ml) was added to the resultant solution, and cooled to 0° C.Methanesulfonyl chloride (0.1 ml) was stirred into the mixture at 0° C.for 1 hour. The reaction solution was poured into a %5 citric acidaqueous solution, and then extracted with ethyl acetate. The resultantorganic layer was dried over magnesium sulfate and concentrated toobtain a mesyl compound. Sodium hydride (58 mg) was suspended inanhydrous DMF (3 ml), and a solution of 1,l-diphenylethanethiol (319 mg)in anhydrous DMF (4 ml) was added to the suspension at 0° C., followedby stirring at room temperature for 1 hour. A solution of the abovemesyl compound in anhydrous DMF (4 ml) was added to the resultantmixture, and the mixture was stirred at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and the residuewas poured into a 5% citric acid aqueous solution, and then extractedwith ethyl acetate. The resultant organic layer was dried over magnesiumsulfate and then concentrated. The resultant residue was purified bycolumn chromatography (silica gel:hexane/ethyl acetate=2/1) to obtainthe object compound (254 mg, yield 50%).

¹H-NMR (300 MHz, CDCl₃) δ2.08 (3H, s), 2.55-2.61 (4H, m), 2.92 (2H, t,J=7.8 Hz), 3.66 (3H, s), 3.81 (2H, t, J=8.1 Hz), 4.52 (2H, s), 6.31 (1H,dd, J=2.1, 7.5 Hz), 6.79-6.87 (2H, m), 7.22-7.34 (6H, m), 7.42-7.45 (4H,m).

IR (liquid film method) 3586, 3056, 2980, 2951, 1890, 1737, 1685, 1609,1591, 1481, 1442, 1400, 1372, 1315, 1242, 1172, 1125, 1092, 1045, 931,823, 763, 742, 701, 661 cm⁻¹

Mass (EI, m/e) 475 (M⁺)

Example 14 Methyl(4-(3-(2-naphthylmethylamino)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

(4-(3-(2-naphthylmethylamino)propyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine(166 mg) was dissolved in DMF (3 ml), and potassium carbonate (63 mg)and methyl bromoacetate (0.045 ml) were added. to the resultant solutionat 0° C., followed by stirring at room temperature for 16 hours. Thereaction solution was diluted with ethyl acetate, washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure, and the residue was purified bycolumn chromatography (silica gel:ethyl acetate/n-hexane=2:3) to obtainthe object compound (140 mg, yield 73%).

Colorless oily substance

¹H-NMR (300 MHz, CDCl₃) δ1.76-1.92 (1H, m), 2.13-2.30 (1H, m), 2.71-2.83(1H, m), 2.86-2.98 (1H, m), 3.00-3.22 (3H, m), 3.28 (1H, ddd, J=12.1,4.9. 2.7 Hz), 3.71 (1H, dd, J=13.7, 9.3 Hz), 3.81 (3H, s), 4.04-4.23(2H, m), 4.35 (1H, dd, J=13.7, 3.0 Hz), 4.46 (1H, br. s), 4.68 (2H, s),6.12 (1H, dd, J=8.2, 1.1 Hz), 6.28 (1H, dd, J=8.2, 1.4 Hz), 6.54 (1H, t,J=8.2 Hz), 7.22 (1H, dd, J=8.4, 1.8 Hz), 7.48-7.84 (2H, m), 7.64 (1H,br. s), 7.69-7.78 (2H, m), 7.81-7.88 (1H, m).

IR (liquid film method) 3217, 2951, 2879, 1757, 1611, 1578, 1484, 1348,1327, 1210, 1174, 1108, 910, 859, 822, 755, 730, 646 cm⁻¹

Mass (EI, m/e) 420 (M⁺)

Example 15 Methyl(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetate

The same process as Example 8 was repeated except that1-(2-(1,1-diphenylethylthio)ethyl)-5-hydroxy-1,2,3,4-tetrahydroquinoline(60 mg) was used to obtain the object compound (51 mg, yield 72%).

¹H-NMR (300 MHz, CDCl₃) δ1.78-1.89 (2H, m), 2.06 (3H, s), 2.47-2.55 (2H,m), 2.69 (2H, t, J=6.6 Hz), 3.04-3.18 (4H, m), 3.78 (3H, s), 4.56 (2H,s), 5.91 (1H, d, J=8.4 Hz), 6.02(1H, d, J=8.4 Hz), 6.86 (1H, t, J=1, 8.4Hz), 7.20-7.35 (6H, m), 7.38-7.47 (4H, m).

IR (liquid film method) 2930, 1763, 1605, 1578, 1493, 1464, 1444, 1336,1286, 1195, 1160, 1123, 1064, 1029, 760, 702 cm⁻¹

Mass (EI, m/e) 461 (M⁺)

Example 16 Methyl(1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetate

Methyl(1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetate(370 mg) was dissolved in methylene chloride (15 ml), and the resultantsolution was stirred at 0° C. Triphenylphosphine (1085 mg) and carbontetrabromide (922 mg) were added to the solution, and the mixture wasstirred at 0° C. After disappearance of the raw materials was confirmed,a saturated sodium bicarbonate aqueous solution (15 ml) was added to thereaction solution, and the mixture was then extracted with ethylacetate. The resultant organic layer was washed with saturated brine,dried over anhydrous sodium sulfate and concentrated. The resultantresidue was purified by column chromatography (silica gel:hexane/ethylacetate=1/1) to obtain a crude product. 1,1-diphenylethanethiol (428 mg)was dissolved in DMF (10 ml) under an argon atmosphere, and theresultant solution was stirred at 0° C. Sodium hydride (65 mg) was addedto the solution, and the mixture was stirred at 0° C. for 5 minutes. Asolution of the crude product in DMF (3 ml) was added to the mixture at0° C. After disappearance of the raw materials was confirmed, thereaction solution was added to a saturated ammonium chloride aqueoussolution (30 ml), and then extracted with ethyl acetate. The resultantorganic layer was washed with saturated brine, dried over anhydroussodium sulfate and concentrated. The resultant residue was purified bycolumn chromatography (silica gel:hexane/ethyl acetate=8/1) to obtainthe object compound (532 mg, yield 84%).

¹H-NMR (300 MHz, CDCl₃) δ1.50-1.68 (4H, m), 2.05 (3H, s), 2.45-2.53 (2H,m), 2.78-2.95 (4H, m), 3.00-3.15 (2H, m), 3.78 (3H, s), 4.59 (2H, s),6.35 (2H, d, J=8.1 Hz), 6.95(1H, t, J=8.1 Hz), 7.17-7.36 (6H, m),7.38-7.44 (4H, m).

IR (liquid film method) 2926, 1765, 1599, 1466, 1444, 1210, 1141, 1114,731, 698 cm⁻¹

Mass (EI, m/e) 475 (M⁺)

Example 17 Methyl(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetate

Methyl (3-(2-(methanesulfonyloxy)ethyl)benzofuran-7-yloxy)acetate (161mg) was dissolved in ethyl acetate (3 ml), and 5% Pd/C (34 mg) andacetic acid (84 μl) were added to the resultant solution, and themixture was stirred at room temperature under a hydrogen atmosphere for13.5 hours. The reaction solution was filtered with Celite, and thefiltrate was concentrated under reduced pressure.

Diphenylmethanethiol (128 mg) was dissolved in DMF (2 ml), and t-BuOK(66 mg) was added to the resultant solution, and the mixture was stirredat room temperature for 5 minutes. A solution of the reaction residue inDMF (1.5 ml) was added to the above solution at room temperature for 10minutes. The reaction solution was poured into a water layer, and thenextracted with ethyl acetate twice. The combined organic layers werewashed with saturated brine, dried over sodium sulfate, and concentratedunder reduced pressure. The resultant residue was purified by columnchromatography (silica gel:n-hexane/ethyl acetate=3/1) to obtain theobject compound (176 mg, yield 83%).

¹H-NMR (300 MHz, CDCl₃) δ1.87-1.76 (1H, m), 2.03-1.91 (1H, m), 2.48-2.42(2H, m), 3.56-3.45 (1H, m), 3.79 (3H, s), 4.59 (1H, t, J=8.8 Hz), 4.13(1H, dd, J=8.8, 6.0 Hz), 4.87 (2H, s), 5.15 (1H, s), 6.91-6.69 (3H, m),7.61-7.20 (10H, m).

IR (KBr method) 3062, 3030, 2954, 1856, 1769, 1622, 1599, 1491, 1454,1377, 1296, 1189, 1114, 1079, 1031, 1002, 953, 911, 830, 752, 704 cm⁻¹

Mass (EI, m/e) 434 (M⁺)

Example 18Methyl(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetate

The same process as Example 17 was repeated except that methyl(3-(2-(methanesulfonyloxy)ethyl)benzofuran-7-yloxy)acetate (284 mg) and1,1-diphenylethanethiol (240 mg) were used to obtain the object compound(310 mg, yield 95%).

¹H-NMR (300 MHz, CDCl₃) δ1.86-1.59 (2H, m), 2.06 (3H, s), 2.41-2.26 (2H,m), 3.50-3.42 (1H, m), 3.78 (3H, s), 4.07 (1H, dd, J=8.8, 6.0 Hz), 4.51(1H, t, J=8.8 Hz), 4.69 (2H, s), 6.76-6.63 (3H, m), 7.44-7.22 (10H, m).

IR (liquid film method) 3060, 3032, 2956, 2932, 1765, 1742, 1622, 1595,1491, 1458, 1444, 1377, 1294, 1216,, 1191, 1114, 1029, 953, 830, 764,743, 700 cm⁻¹

Mass (EI, m/e) 448 (M⁺)

Example 19 Methyl(+)-3-(2-(3-(2hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetate

(+)-3-(2-hydroxyethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid (180 mg)was dissolved in dichloromethane (3 ml), and cooled to 0° C.Triethylamine (0.072 ml) and methanesulfonyl chloride (0.15 ml) wereadded to the resultant solution, and the mixture was stirred at 0° C.for 30 minutes. The reaction solution was poured into water, and thenextracted with ethyl acetate twice. The combined organic layers werewashed with saturated brine, and dried over sodium sulfate. Sodiumsulfate was filtered off, and the filtrate was concentrated.

3-(2-methoxymethoxyphenyl)propanethiol (197 mg) was dissolved indimethylformamide (5 ml), and potassium t-butoxide (96 mg) was added tothe resultant solution, and the mixture was stirred at room temperaturefor 10 minutes. A solution of the previously prepared mesylate indimethylformamide (2 ml) was added to the reaction solution, and themixture was stirred at room temperature for 50 minutes. The reactionsolution was poured into water, and the extracted with ethyl acetatetwice. The combined organic layers were washed with saturated brine, anddried over sodium sulfate. Sodium sulfate was filtered off, and thefiltrate was concentrated. The residue was dissolved in methanol (5 ml),and a 2N HCl/methanol solution (0.5 ml) was added to the resultantsolution, and the mixture was stirred at room temperature for 19 hours.The reaction solution was concentrated, and the residue was purified byflash column chromatography using silica gel (elutionsolvent:hexane/ethyl acetate=2/1) to obtain the object compound (168 mg,yield 64%).

¹H-NMR (300 MHz, CDCl₃) δ1.80-2.07 (4H, m), 2.51-2.60 (4H, m), 2.73 (2H,t, J=7.1 Hz), 3.54-3.63 (1H, m), 3.80 (3H, s), 4.30 (1H, dd, J=5.8, 9.1Hz), 4.69 (1H, t, J=9.1 Hz), 4.73 (2H, s), 5.42 (1H, s), 6.71-6.89 (5H,m), 7.12-7.06 (2H, m).

IR (KBr method) 3433, 2949, 1744, 1592, 1488, 1456, 1232, 1187, 1114,755 cm⁻¹

Mass (EI, m/e) 402 (M⁺)

Example 20(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(439 mg) was dissolved in methanol (8.0 ml), and a 4.89N sodiumhydroxide aqueous solution (0.60 ml) was added to the resultantsolution, and the mixture was stirred at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and the residuewas poured into a 5% citric acid aqueous solution, and then extractedwith ethyl acetate. The resultant organic layer was washed with waterand saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was recrystallized from ethyl acetate/n-hexaneto obtain the object compound (381 mg, yield 90%).

Colorless needle crystal: mp. 172.5° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.60 (2H, m), 3.27 (2H, t, J=4 Hz), 3.37 (2H,m), 4.24 (2H, t, J=4 Hz), 4.61 (2H, s), 5.23 (1H, s), 6.10 (1H, dd, J=1,8 Hz), 6.31 (1H, dd, J=1, 8 Hz), 6.66 (1H, t, J=8 Hz), 7.22-7.37 (6H,m), 7.42-7.46 (4H, m).

IR (KBr method) 3030, 2989, 2590, 1743, 1610, 1576, 1487, 1451, 1431,1348, 1259, 1240, 1214, 1186, 1160, 1131, 1102, 1081, 1048, 752, 703cm⁻¹

Mass (EI, m/e) 435 (M⁻¹⁾

Elemental analysis Calcd C: 68.94% H: 5.79% N: 3.22% S: 7.36% Found C:68.85% H: 5.77% N: 3.24% S: 7.25%

Example 21(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 20 was repeated except that methyl(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(915 mg) was used to obtain the object compound (682 mg, yield 77%).

Colorless needle crystal: mp. 161-161.5° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.06 (3H, s), 2.52 (2H, t, J=7.5 Hz), 3.14 (2H,t, J=7.5 Hz), 3.22 (2H, t, J=4.5 Hz), 4.23 (2H, t, J=4.5 Hz), 4.61 (2H,s), 6.06 (1H, dd, J=1, 8 Hz), 6.31 (1H, dd, J=1, 8 Hz), 6.68 (1H, t, J=8Hz), 7.22-7.35 (6H, m), 7.39-7.44 (4H, m).

IR (KBr method) 3450, 3058, 2928, 1744, 1609, 1506, 1489, 1433, 1348,1241, 1214, 1187, 1162, 1131, 754, 737, 723, 698 cm⁻¹

Mass (EI, m/e) 449 (M⁺)

Elemental analysis Calcd C: 69.46% H: 6.05% N: 3.12% S: 7.13% Found C:69.70% H: 6.17% N: 3.15% S: 7.45%

Example 22(4-(2-(1,1-diphenyl-2,2,2-trifluoroethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4-(2-(1,1-diphenyl-2,2,2-trifluoroethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(585 mg) was dissolved in ethanol (15 ml), and a 4.89N sodium hydroxideaqueous solution (0.50 ml) was added to the resultant solution, and themixture was stirred at room temperature for 3 hours. The solvent wasdistilled off under reduced pressure, and the residue was poured into a5% citric acid aqueous solution, and then extracted with ethyl acetate.The resultant organic layer was washed with water and saturated brine,dried over magnesium sulfate, and then concentrated. The residue wasrecrystallized from ethyl acetate/n-hexane to obtain the object compound(472 mg, yield 83%).

Colorless plate crystal: mp. 140-140.5° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.56 (2H, t, J=7.5 Hz), 3.19 (4H, m), 4.23 (2H,m), 4.61 (2H, s), 5.98 (1H, dd, J=1, 8 Hz), 6.30 (1H, dd, J=1, 8 Hz),6.65 (1H, t, J=8 Hz), 7.32-7.36 (6H, m), 7.42-7.46 (4H, m).

IR (KBr method) 3430, 3040, 2894, 1748, 1611, 1502, 1487, 1448, 1435,1348, 1243, 1216, 1187, 1149, 1129, 750, 716, 698 cm⁻¹

Mass (EI, m/e) 503 (M⁺)

Elemental analysis Calcd C: 61.58% H: 4.85% N: 2.76% S: 6.32% F: 11.24%Found C: 61.68% H: 4.85% N: 2.87% S: 6.54% F: 11.37%

Example 23(4-(2-(1,1-bis-(4-fluorophenyl)ethylthio)-ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 20 was repeated except that methyl(4-(2-(1,1-bis-(4-fluorophenyl)ethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(254 mg) was used to obtain the object compound (166 mg, yield 67%).

Colorless needle crystal: mp. 142-143° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.02 (3H, s), 2.50 (2H, t, J=7.6 Hz), 3.21 (2H,t, J=7.6 Hz), 3.26 (2H, t, J=7.6 Hz), 4.25 (2H, t, J=4.4 Hz), 4.62 (2H,s), 6.06 (1H, dd, J=8.2, 1.1 Hz), 6.31 (1H, dd, J=8.2, 1.1 Hz), 6.69(1H, t, J=8.2 Hz), 6.95-7.03 (4H, m), 7.33-7.40 (4H, m).

IR (KBr method) 2926, 1744, 1715, 1611, 1504, 1454, 1431, 1346, 1238,1214, 1187, 1162, 1131,. 1108, 1064, 832, 756 cm⁻¹

Mass (EI, m/e) 485 (M⁺)

Elemental analysis Calcd C: 64.32% H: 5.19% N: 2.88% S: 6.60% Found C:64.22% H: 5.13% N: 2.99% S: 6.61%

Example 24(4-(2-(1-methyl-1-phenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 20 was repeated except that methyl(4-(2-(1-methyl-1-phenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(358 mg) was used to obtain the object compound (271 mg, yield 78%).

Colorless needle crystal: mp. 114° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.72 (6H, s), 2.42 (2H, m), 3.10 (2H, m), 3.19(2H, t, J=4.5 Hz), 4.22 (2H, t, J=4.5 Hz), 4.60 (2H, s), 5.98 (1H, dd,J=1, 8 Hz), 6.29 (1H, dd, J=1, 8 Hz), 6.66 (1H, t, J=8 Hz), 7.24 (1H,m), 7.35 (2H, m), 7.56 (2H, m).

IR (KBr method) 2962, 2924, 1744, 1611, 1506, 1487, 1433, 1350, 1245,1212, 1187, 1164; 1129, 752, 705, 698 cm⁻¹

Mass (EI, m/e) 387 (M⁺)

Elemental analysis Calcd (+0.3H₂O) C: 64.20% H: 6.57% N: 3.56% S: 8.16%Found C: 64.12% H: 6.51% N: 3.57% S: 8.03%

Example 25(4-(2-(benzylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy) aceticacid

Methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(242 mg) was dissolved in methylene chloride (5 ml), and the resultantsolution was cooled to 0° C. Triethylamine (0.38 ml) and methanesulfonylchloride (0.10 ml) were added to the solution, and the mixture wasstirred at 0° C. for 1 hour. The reaction solution was poured into a 3%citric acid aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was washed with water and saturated brine, driedover sodium sulfate, and then concentrated to obtain the mesyl compound.

Anhydrous DMF (15 ml) was added to sodium hydride (72 mg) to form asuspension, and a solution of phenylmethanethiol (0.5 ml) in anhydrousDMF (1 ml) was added to the suspension at 0° C., followed by stirring atroom temperature for 30 minutes. A solution of the above mesyl compoundin anhydrous DMF (1 ml) was added to the resultant mixture at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure, and the residue was poured into a 3% citric acid aqueoussolution, and then extracted with ethyl acetate. The resultant organiclayer was washed with water and saturated brine, dried over sodiumsulfate, and then concentrated. The residue was recrystallized fromethyl acetate/n-hexane to obtain the object compound (199 mg, yield61%).

Colorless needle crystal: mp. 127-131° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.61 (2H, t, J=7.6 Hz), 3.30-3.38 (4H, m), 3.76(2H, s), 4.27 (2H, t, J=4.4 Hz), 4.63 (2H, s), 6.25 (1H, dd, J=8.2, 1.1Hz), 6.32 (1H, dd, J=8.2, 1.1 Hz), 6.72 (1H, t, J=8.2 Hz), 7.25-7.35(5H, m).

IR (KBr method) 2898, 1742, 1711, 1611, 1576, 1506, 1487, 1456, 1431,1350, 1325, 1263, 1241, 1214, 1187, 1160, 1129, 1104 cm⁻¹

Mass (EI, m/e) 359 (M⁺)

Elemental analysis Calcd C: 63.49% H: 5.89% N: 3.90% S: 8.92% Found C:63.20% H: 5.90% N: 3.97% S: 8.78%

Example 26

(4-(2-(2,2-diphenylpropylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 20 was repeated except that methyl(4-(2-(2,2-diphenylpropylthio)ethyl)-3,4-dihydro-2H-1,4benzoxazin-8-yloxy)acetate(119 mg) was used to obtain the object compound (85 mg, yield 74%).

Colorless needle crystal: mp. 138-139° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.78 (3H, s), 2.35 (2H, t, J=7.1 Hz), 3.24-3.33(6H, m), 4.23 (2H, t, J=4.4 Hz), 4.62 (2H, s), 6.28-6.33 (2H, m), 6.76(1H, t, J=8.2 Hz), 7.17-7.31 (10H, m).

IR (KBr method) 3514, 3428, 3392, 2926, 1742, 1611, 1576, 1508, 1487,1460, 1435, 1350, 1245, 1212, 1187, 1164, 1129, 1046, 754, 700 cm⁻¹

Mass (EI, m/e) 463 (M⁺)

Example 27(4-(2-(1,1-bis-(3-thienyl)ethylthio)ethyl-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4-(2-(1,1-bis-(3-thienyl)ethylthio)ethyl-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(183 mg) was dissolved in THF (1 ml) and methanol (2 ml), and a 2Nsodium hydroxide aqueous solution (0.4 mL) was added to the resultantsolution at room temperature for 20 minutes. The solvent was distilledoff under reduced pressure, and the residue was poured into a 5% citricacid aqueous solution, and then extracted with ethyl acetate. Theresultant organic layer was washed with water and saturated brine, driedover sodium sulfate, and then concentrated. The residue wasrecrystallized from ethyl acetate/n-hexane to obtain the colorlessgranular object compound (161 mg, yield 91%).

Colorless granular crystal: mp. 149° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.05 (3H, s), 2.54 (2H, t, J=7.4 Hz), 3.17 (2H,t, J=7.4 Hz), 3.25 (2H, t, J=4.4 Hz), 4.25 (2H, t, J=4.4 Hz), 4.62 (2H,s), 6.11 (1H, dd, J=8.2, 1.1 Hz), 6.31 (1H, dd, J=8.2, 1.1 Hz), 6.72(1H, t, J=8.2 Hz), 7.12 (2H, dd, J=3.0, 1.4 Hz), 7.14 (2H, dd, J=5.2,1.4 Hz), 7.29 (2H, dd, J=5.2, 3.0 Hz).

IR (KBr method) 3432, 3092, 2970, 2922, 1744, 1715, 1700, 1607, 1574,1506, 1487, 1464, 1456, 1437, 1431, 1371, 1352, 1330, 1278, 1251, 1241,1212, 1189, 1170, 1127, 1683, 1042 cm⁺¹

Mass (EI, m/e) 461 (M⁺)

Elemental analysis Calcd (+0.4H₂O) C: 56.36% H: 5.12% N: 2.99% S: 20.52%Found C: 56.34% H: 5.04% N: 3.03% S: 20.45%

Example 28(4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(320 mg) was dissolved in THF (1 ml) and methanol (2 ml), and a 2Nsodium hydroxide aqueous solution (0.9 ml) was added to the resultantsolution, and the mixture was stirred at room temperature for 1 hour.The solvent was distilled off under reduced pressure, and the residuewas poured into a 5% citric acid aqueous solution, and then extractedwith ethyl acetate. The resultant organic layer was washed with waterand saturated brine, dried over sodium sulfate, and then concentrated.The residue was recrystallized from ethyl acetate/n-hexane to obtaincolorless needle crystals of the object compound (221 mg, yield 71%).

Colorless needle crystal: mp. 112-113° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ3.48 (2H, t, J=4.4 Hz), 3.54 (2H, t, J=5.4 Hz),3.65 (2H, t, J=5.4 Hz), 4.26 (2H, t, J=4.4 Hz), 4.64 (2H, s), 5.34 (1H,s), 6.32 (1H, dd; J=8.2, 1.2 Hz), 6.41 (1H, dd, J=8.2, 1.2 Hz), 6.73(1H, t, J=8.2 Hz), 7.20-7.32 (10H, m).

IR (KBr method) 2894, 2866, 2678, 1744, 1613, 1576, 1506, 1489, 1454,1439, 1350, 1328, 1278, 1247, 1212, 1189, 1152, 1110, 1079, 754, 741,698 cm⁻¹

Mass (EI, m/e) 419 (M⁺)

Elemental analysis Calcd C: 71.58% H: 6.01% N: 3.34% Found C: 71.22% H:5.98% N: 3.40%

Example 29(4-(2-(1,1-diphenylethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 28 was repeated except that methyl(4-(2-(1,1-diphenylethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(308 mg) was used to obtain the object compound (193 mg, yield 65%).Colorless granular crystal: mp. 108° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.83 (3H, s), 3.40-3.51 (6H, m), 4.27 (2H, t,J=4.4 Hz), 4.63 (2H, s), 6.30 (1H, dd, J=8.2, 1.1 Hz), 6.33 (1H, dd,J=8.2, 1.1 Hz), 6.69 (1H, t, J=8.2 Hz), 7.17-7.33 (10H, m).

IR (KBr method) 3060, 2986, 2910, 2876, 1746, 1613, 1578, 1489, 1448,1437, 1348, 1241, 1214, 1187, 1151, 1106, 1075, 1052, 768, 758, 700 cm⁻¹

Mass (EI, m/e) 433 (M⁺)

Example 30(4-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(308 mg) was dissolved in THF (1 ml) and methanol (2 ml), and a 2Nsodium hydroxide aqueous solution (0.8 ml) was added to the resultantsolution, and the mixture was stirred at room temperature for 20minutes. The solvent was distilled off under reduced pressure, and theresidue was poured into a 5% citric acid aqueous solution, and thenextracted with ethyl acetate. The resultant organic layer was washedwith water and saturated brine, dried over sodium sulfate, and thenconcentrated. The residue was recrystallized from ethyl acetate/n-hexaneto obtain colorless granular crystals of the object compound (249 mg,yield 79%). Colorless granular crystal: mp. 133° C. (recrystallized fromethyl acetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.36-1.48 (2H, m), 1.63 (3H, s), 2.08-2.17 (2H,m), 3.16 (2H, t, J=8.4 Hz), 3.21 (2H, t, J=4.4 Hz), 4.25 (2H, t, J=4.4Hz), 4.62 (2H, s), 6.26 (1H, d, J=8.5 Hz), 6.30 (1H, d, J=8.0 Hz), 6.71(1H, t, J=8.2 Hz), 7.16-7.22 (6H, m), 7.23-7.31 (4H, m).

IR (KBr method) 3424, 2932, 2876, 1744, 1613, 1576, 1489, 1462, 1435,1371, 1350; 1325, 1245, 1209, 1187, 1164, 1137, 1110, 1042, 1029, 911,890, 752, 708 cm⁻¹

Mass (EI, m/e) 431 (M⁺)

Elemental analysis Calcd (+0.25H₂O) C: 74.37% H: 6.82% N: 3.21% Found C:74.36% H: 6.81% N: 3.21%

Example 31(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

The same process as Example 26 was repeated except that methyl(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(170 mg) was used to obtain the object compound (155 mg, yield 94%).Colorless powder: mp. 106° C. (recrystallized fromdichloromethane/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ2.08 (3H, s), 2.57 (2H, m), 3.81 (2H, m), 4.60(2H, s), 4.70 (2H, s), 6.16 (1H, dd, J=1, 8 Hz), 6.61 (1H, dd, J=1, 8Hz), 6.84 (1H, t, J=8 Hz), 7.21-7.34 (6H, m), 7.40-7.45 (4H, m).

IR (KBr method) 3038, 2924, 1734, 1655, 1611, 1591, 1485, 1421, 1232,1199, 1149, 1052, 766, 737, 700 cm⁻¹

Mass (EI, m/e) 463 (M⁺)

Elemental analysis Calcd (+1.0H₂O) C: 64.85% H: 5.65% N: 2.91% S: 6.66%Found C: 65.02% H: 5.46% N: 2.76% S: 6.49%

Example 32(4-((diphenylmethylcarbamoyl)methyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

Methyl(4-((diphenylmethylcarbamoyl)methyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate(260 mg) was suspended in a solvent mixture of methanol (20 ml) and THF(10 ml), and the resultant suspension was stirred at room temperature. A1N sodium hydroxide aqueous solution (2 ml) was added to the resultantsolution, and the mixture was stirred at room temperature for 3 hours,followed by concentration. Water (60 ml) was added to the residue, and1N hydrochloric acid was added to the mixture to adjust pH to 3,followed by extraction with ethyl acetate. The resultant organic layerwas washed with saturated brine, dried over sodium sulfate, and thenconcentrated. The residue was recrystallized from ethyl acetate/n-hexaneto obtain the object compound (194 mg, yield 77%). mp. 232.0-234.0° C.

¹H-NMR (300 MHz, DMSO-d₆) δ4.66 (4H, s), 4.69 (2H, s), 6.10 (1H, d,J=8.4 Hz), 6.60 (1H, dd, J=1.2, 8.4 Hz), 6.67 (1H, dd, J=1.2, 8.4 Hz),6.89 (1H, t, J=8.4 Hz), 7.22-7.38 (10H, m), 9.16 (1H, d J=8.7 Hz).

IR (KBr method) 3300, 1737, 1682, 1660, 1612, 1541, 1484, 1400, 1286,1236, 1192, 1160, 1106, 1057, 974, 862, 765, 699 cm⁻¹

Mass (EI, m/e) 446 (M⁺)

Elemental analysis Calcd C: 67.26% H: 4.97% N: 6.27% Found C: 67.11% H:5.09% N: 6.33%

Example 333-(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)propionicacid

Methyl3-(4-(2-(1,1-diphenylethylthio)ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)propionate(245 mg) was dissolved in a solvent mixture of ethanol (2.0 ml) and THF(2.0 ml), and a 1.0N sodium hydroxide aqueous solution (1.1 ml) wasadded to the resultant solution, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distilled off under reducedpressure, and a 1.0N hydrochloric acid aqueous solution (1.1 ml) wasadded to the residue. The mixture was diluted with water, and thenextracted with ethyl acetate. The resultant organic layer was dried overmagnesium sulfate, and then concentrated. The residue was recrystallizedfrom ethyl acetate/n-hexane to obtain the object compound (169 mg, yield70%). mp. 110.1° C. (recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CD₃OD) δ2.03 (3H, s), 2.53-2.58 (4H, m), 2.89 (2H, t,J=7.5 Hz), 3.87 (2H, t, J=7.7 Hz), 4.54 (2H, s), 6.47 (1H, dd, J=1.7,8.0 Hz), 6.83-6.92 (2H, m), 7.18-7.30 (6H, m), 7.36-7.40 (4H, m).

IR (KBr method) 3448, 3052, 1685, 1590, 1480, 1443, 1398, 1319, 1219,1126, 1092, 1034, 954, 823, 743, 701, 559, 491 cm⁻¹

Mass (EI, m/e) 461 (M⁺)

Elemental analysis Calcd C: 70.26% H: 5.90% N: 3.03% S: 6.95% Found C:70.35% H: 5.80% N: 2.97% S: 7.03%

Example 34(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)aceticacid

Methyl(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetate(268 mg) was dissolved in methanol (10 ml) and THF (5 ml), and theresultant solution was stirred at room temperature. A 1N sodiumhydroxide aqueous solution (1.00 ml) was added to the solution, and themixture was stirred at room temperature. After disappearance of the rawmaterials was confirmed, the solvent was distilled off under reducedpressure. Water (20 ml) was added to the residue, and the resultantmixture was. neutralized with 1N hydrochloric acid (1.00 ml), and thenextracted with ethyl acetate. The resultant organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated. The residue was recrystallized from methylenechloride/hexane to obtain the object compound (173 mg, yield 67%).

Pale yellow needle crystal: mp. 150.5-152.0° C.

¹H-NMR (300 MHz, CDCl₃) δ1.80-190 (2H, m), 2.06 (3H, s), 2.47-2.55 (2H,m), 2.67 (2H, t, J=6.6 Hz), 3.04-3.19 (4H, m), 4.61 (2H, s), 5.93 (1H,d, J=8.1 Hz), 6.05 (1H, d, J=8.1 Hz), 6.88 (1H, t, J=8.1 Hz), 7.20-7.34(6H, m), 7.39-7.46 (4H, m).

IR (KBr method) 1744, 1745, 1605, 1574, 1493, 1466, 1433, 1249, 1201,1164, 1127, 1062, 1029, 913, 756, 698 cm⁻¹

Mass (FAB, m/e) 448 (M+H⁺)

Example 35(1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-benzazepin-6-yloxy)aceticacid

The same process as Example 34 was repeated except that methyl(1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetate(283 mg) was used to obtain the object compound (171 mg, yield 62%).

¹H-NMR (300 MHz, CDCl₃) δ1.68-1.52 (4H, m), 2.05 (3H, s), 2.45-2.53 (2H,m), 2.80-2.91 (4H, m), 3.06-3.14 (2H, m), 4.63 (2H, s), 6.39 (2H, d,J=8.1 Hz), 6.97 (1H, t, J=8.1 Hz), 7.16-7.32 (6H, m), 7.36-7.44 (4H, m).

IR (liquid film method) 2928, 1734, 1597, 1580, 1464, 1444, 1220, 1187,1139, 1114, 1029, 909, 731, 698 cm⁻¹

Mass (EI, m/e) 461 (M⁺)

Example 36(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

Methyl(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetate(205 mg) was dissolved in methanol/THF (4/1.5 ml), and a 2N sodiumhydroxide aqueous solution (0.4 ml) was added to the resultant solution,and the mixture was stirred at room temperature for 30 minutes. Thereaction solution was neutralized with 1N hydrochloric acid, poured intoa water layer, and then extracted with ethyl acetate (10 ml) twice. Thecombined organic layers were washed with saturated brine, dried oversodium sulfate, and then concentrated under reduced pressure. Theresidue was purified by column chromatography (DIOL, n-hexane/diethylether=1/2) to obtain the object compound (105 mg, yield 53%).

mp. 88-89° C. (recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, CDCl₃) δ1.86-1.74 (1H, m), 2.02-1.90 (1H, m), 2.45 (2H,t, J=7.4 Hz), 3.57-3.47 (1H, m), 4.13 (1H, dd, J=8.8, 6.0 Hz), 4.59 (1H,t, J=8.8 Hz), 4.71 (2H, s), 5.15 (1H, s), 6.77-6.72 (3H, m), 7.44-7.20(10H, m).

IR (KBr method) 3482, 3360, 1736, 1711, 1624, 1593, 1491, 1460, 1450,1435, 1267, 1191, 1118, 1079, 961, 940, 770, 748, 731, 702 cm⁻¹

Mass (EI, m/e) 420 (M⁺)

Elemental analysis Calcd C: 71.40% H: 5.75% S: 7.63% Found C: 71.11% H:5.76% S: 7.63%

Example 37(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)aceticacid

The same process as Example 36 was repeated except that methyl(3-(2-(1,1-diphenylethylthio)ethyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetate(360 mg) was used to obtain the object compound (313 mg, yield 90%).

m.p 65-67° C. (recrystallized from n-hexane/chloroform)

¹H-NMR (300 MHz, CDCl₃) δ1.88-1.60 (2H, m), 2.06 (3H, s), 2.41-2.26 (2H,m), 3.51-3.41 (1H, m), 4.07 (1H, dd, J=8.8, 6.0 Hz), 4.51 (1H, t, J=8.8Hz), 4.70 (2H, s), 6.78-6.66 (3H, m), 7.44-7.21 (10H, m).

IR (KBr method) 3492, 3376, 3060, 3032, 2972, 2932, 1719, 1624, 1595,1492, 1462, 1399, 1375, 1322, 1269, 1192, 1117, 1060, 1029, 957, 828,762, 733 cm⁻¹

Mass (EI, m/e) 434 (M⁺)

Elemental analysis Calcd C: 69.00% H: 6.24% S: 7.09% Found C: 69.09% H:6.19% S: 7.04%

Example 38(4-(2-(1,1-diphenylethylsulfinyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid

(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)aceticacid (51 mg) was dissolved in methylene chloride (5 ml), and theresultant solution was stirred at room temperature. m-CPBA (20 mg) wasthen added to the solution, and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was added to water (20ml), and then extracted with ethyl acetate. The resultant organic layerwas washed with saturated brine, dried over sodium sulfate, andconcentrated. The residue was purified by Lober® column chromatography(DIOL, type A, developing solvent: n-hexane/ethyl acetate=1/2) to obtainthe object compound (43 mg, yield 81%).

¹H-NMR (300 MHz, CDCl₃) δ1.97 (3H, s), 2.26-2.46 (2H, m), 3.20-3.37 (2H,m), 3.52-3.60 (2H, m), 4.22-4.27 (2H, m), 4.64 (2H, s), 6.15 (1H, dd,J=1.2, 8.4 Hz), 6.30 (1H, dd, J=1.2, 8.4 Hz, 6.65(1H, t, J=8.4 Hz),7.27-7.46 (10H, m).

Mass (FAB, m/e) 466 (M+H)⁺

Example 39 Sodium(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

A 0.0978N sodium hydroxide aqueous solution (11.54 ml) and distilledwater (10 ml) were added to(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzooxazine-8-yloxy)aceticacid (510 mg), and the mixture was heated to form a solution. Thesolution was filtered with a membrane filter, and the residue was washedwith 10 ml of distilled water. The filtrate was freeze-dried to obtainthe object compound (535 mg, yield 100%).

Colorless amorphous mp. 110° C.

¹H-NMR (300 MHz, D₂O, 30° C.) δ1.79 (3H, s), 2.24 (2H, m), 2.75 (4H, m),3.86 (2H, m), 4.23 (2H, s), 5.66 (1H, br), 6.08 (1H, br), 6.37 (1R, br),7.00 (6H, m), 7.23 (4H, m).

IR (KBr method) 3400, 2926, 1742, 1620, 1585, 1475, 1433, 1272, 1212,1108, 1062, 1017, 1007, 826 cm⁻¹

Mass (FAB-Pos, m/e) 472 (M+H)⁺, 494 (M+Na)⁺

Elemental analysis Calcd (+1.6H₂O) C: 62.41% H: 5.88% N: 2.80% S: 6.41%Found C: 62.35% H: 5.77% N: 3.02% S: 6.59%

Example 40 Megluminium(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate

Meglumine (243 mg) was suspended in ethanol (24 ml), and then heated toform a solution.(4-(2-(1,1-diphenylethylthio)ethyl-3,4-dihydro-2H-1,4-benzooxazine-8-yloxy)aceticacid (500 mg) was dissolved in ethanol (50 ml) by heating, and thethus-obtained solution was added to the meglumine solution, and themixture was allowed to stand at room temperature. The precipitated solidwas filtered off to obtain the object compound (671 mg, yield 94%).

mp. 137.0-141.5° C.

¹H-NMR (500 MHz, DMSO-d₆) δ2.04 (3H, s), 2.45 (3H, s), 2.42-2.52 (2H,m), 2.85 (1H, dd, J=8.5, 12.5 Hz), 2.94 (1H, dd, J=3.5, 12.5 Hz), 3.13(2H, t, J=7.8 Hz), 3.16 (2H, t, J=4.3 Hz), 3.36-3.44 (2H, m), 3.46-3.52(1H, m), 3.58 (1H, dd, J=3.5, 11.0 Hz), 3.65 (1H, dd, J=1.5, 5.0 Hz),3.81-3.87 (1H, m), 4.05 (2H, t, J=4.0 Hz), 4.16 (2H, s), 5.88 (1H, d,J=7.5 Hz), 6.09 (1H, dd, J=1.0, 8.5 Hz), 6.50 (1H, t, J=8.3 Hz),7.22-7.28 (2H, m), 7.30-7.42 (8H, m).

Mass (FAB, m/e) 448 (M−H)⁻

Elemental analysis Calcd C: 61.47% H: 6.88% N: 4.34% S: 4.97% Found C:61.22% H: 6.80% N: 4.36% S: 4.99%

Example 41 Diethanolammonium(+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetate

Methyl(+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetate(160 mg) was dissolved in methanol (4 ml), and a 2N sodium hydroxideaqueous solution (0.4 ml) was added to the resultant solution, and themixture was stirred at room temperature for 1.5 hours. The reactionsolution was poured into water and then extracted with ethyl acetatetwice. The combined organic layers were washed with saturated brine, anddried over sodium sulfate. Sodium sulfate was filtered off, and thefiltrate was concentrated. The residue was purified by Lober® columnDIOL (elution solvent: hexane/ethyl acetate=1/2) to obtain(+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyaceticacid (145 mg). This product was dissolved in chloroform, anddiethanolamine was added to the resultant solution. The solvent wasdistilled off under reduced pressure, and the residue was recrystallizedfrom hexane/ethanol to obtain the object compound (140 mg, yield 76%).

[α]_(D) 20=+38.24 (c=0.570, MeOH)

mp. 107-109° C. (recrystallized from ethyl acetate/n-hexane)

¹H-NMR (300 MHz, D₂O) δ1.60-1.85 (4H, m), 2.33-2.48 (4H, m), 2.58 (2H,t, J=7.1 Hz), 3.19-3.23 (4H, m), 3.36-3.45 (1H, m), 3.83-3.86 (4H, m),4.15 (1H, dd, J=6.3, 9.1 Hz), 4.54(1H, t, J=9.1 Hz), 6.64-6.84 (5H, m),7.02-7.06 (2H, m).

IR (KBr method) 3276, 2941, 1618, 1372, 1490, 1455, 1430, 1372, 1326,1282, 1190, 1077, 1043, 951 cm⁻¹

Mass (EI, m/e) 388 (M⁺)

Example 42 Platelet Aggregation Inhibiting Action 1

The blood collected from the human medial cubital vein was centrifugedat 800 rpm for 10 minutes, and the upper portion was collected asplatelet-rich plasma (PRP). PRP was dispensed to small test tubes, andTXA₂ agonist U-46619 was added thereto (the final concentration 1 to 4μM) to induce platelet aggregation. The degree of platelet aggregationwas measured as a change in turbidity by a platelet aggregationmeasuring device (Hematracer 1, Nikko Bioscience). Each compound wasadded 1 minute before the addition of U-46619, and a concentration atwhich aggregation was 50% inhibited was calculated as a IC50 value.

The activities of the compounds of the present invention were evaluatedby the above method. The results are summarized in Table 1.

TABLE 1 Platelet aggregation Example No. inhibiting action IC50 (μM) 201.3 21 0.55 28 5.7 29 5.5 34 0.59 36 0.55 37 0.49

Example 43 Platelet Aggregation Inhibiting Action 2

The blood collected from the human medial cubital vein was centrifuged800 rpm for 10 minutes, and the upper portion was collected asplatelet-rich plasma (PRP). PRP was dispensed to small test tubes, andADP was added thereto (the final concentration 1 to 10 μM) to induceplatelet aggregation. The degree of platelet aggregation was measured asa change in turbidity by a platelet aggregation measuring device(Hematracer 1, Nikko Bioscience). Each compound was added 1 minutebefore the addition of ADP, and a concentration at which aggregation was50% inhibited was calculated as IC50 value.

The activities of the compounds of the present invention were evaluatedby the above method. The results are summarized in Table 2.

TABLE 2 Platelet aggregation Example No. inhibiting action IC50 (μM) 202.0 21 1.8 28 16 29 16 34 1.3 36 0.95 37 1.8

Example 44 TXA₂ Receptor Binding Test

The blood collected from the human antebrachial vein and 1/10 volume ofACD solution (85 mM trisodium citrate, 65 mM citric acid, 2% glucose)were mixed, and 8 ml of the mixture was dispensed to each of Spitztubes. The platelet-rich plasma obtained by centrifugation at roomtemperature and 200×g for 10 minutes was further centrifuged at 1000×gfor 15 minutes to obtain platelets. The thus-obtained platelets werecentrifugally washed with a cleaning buffer (115 mM sodium chloride, 4.3mM potassium dihydrogen phosphate, 5.5 mM glucose, 1 mM disodium EDTA,10 μM indomethane, pH 6.5), and 1 ml of a dissolution buffer (10 mMtris(hydroxymethyl)aminomethane, 5 mM magnesium chloride, 2 mM disodiumEDTA, pH 7.4) was added to-the platelets, followed by three times offreezing in liquid nitrogen and melting at room temperature to crush theplatelets. The crushed platelets were cleaned by three times ofultracentrifugation (40000×g, 20 minutes each) using 5 mm ice-coldtris-hydrochloric acid buffer. The finally obtained sediment was used asa platelet membrane fraction.

As a TXA₂ receptor ligand, tritium-labeled SQ29548 ([³H]SQ29548) wasused. As a solvent for receptor binding reaction, a 50 mMtris-hydrochloric acid buffer (5 nM magnesium chloride, pH 7.4) wasused. A saturation test was conducted by reaction of [³H]SQ29548 (100μl) at a final concentration of 3 to 100 nM and 0.1 mg protein/ml ofplatelet membrane fraction suspension (100 μl) at 25° C. for 30 minutesunder shaking. Competitive experiment was carried out by reaction of amixed solution (100 μl) of a test compound dissolved in an appropriatesolvent and diluted and [³H]SQ29548 at a final concentration of 10 nM,and 0.1 mg protein/ml of platelet membrane fraction suspension (100 μl)at 25° C. for 30 minutes under shaking. After the completion ofreaction, the membrane fraction was recovered on a glass filter by acell harvester, and washed with an ice-cold buffer. Then, radioactivitywas measured by a scintillation counter. Nonspecific binding to asubstance other than the receptor was determined by reaction in thepresence of SQ29548 at a final concentration of 10 nM. In thecompetitive experiment, IC50 value and Hill coefficient of each of thetest compounds were determined by pseudo-Hill plots, and the receptordissociation constant (Ki value) was determined from the IC50 value andthe receptor dissociation constant (Kd value) of [³H]SQ29548, which wasobtained by saturation experiment, according to the following equation:

Ki value=IC50 value/[1+(radioactive ligand concentration/Kd value)]

The activities of the compounds of the present invention were evaluatedby the above method. The results summarized in Table 3.

TABLE 3 TXA₂ receptor affinity Example No. Ki (μM) 21 0.050 34 0.12 360.070

Example 45 PGI₂ Receptor Binding Experiment

As a PGI₂ receptor ligand, tritium-labeled (1R, 2R, 3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octene-6-ynyl]-1H-cyclopenta[b]benzofuran-4-butanoic acid (compound A) was used. A saturation testwas conducted by reaction of compound A (100 μl) at a finalconcentration of 3 to 100 nM and 0.1 mg protein/ml of platelet membranefraction suspension (100 μl) at 4° C. for 60 minutes under shaking.Competitive experiment was carried out by reaction of a mixed solution(100 μl) of a test compound dissolved in an appropriate solvent anddiluted and compound A at a final concentration of 10 nM, and 0.1 mgprotein/ml of platelet membrane fraction suspension (100 μl) at 4° C.for 60 minutes under shaking. After the completion of reaction, themembrane fraction was recovered on a glass filter by a cell harvester,and washed with an ice-cold buffer. Then, radioactivity was measured bya scintillation counter. Nonspecific binding to a substance other thanthe receptor was determined by reaction in the presence of beraprostsodium at a final concentration of 10 nM. In the competitive experiment,IC50 value and Hill coefficient of each of test compounds weredetermined by pseudo-Hill plots, and the receptor dissociation constant(Ki value) was determined from the IC50 value and the receptordissociation constant (Kd value) of compound A, which was obtained bysaturation experiment, according to the following equation:

Ki value=IC50 value/[1+(radioactive ligand concentration/Kd value)]

The activities of the compounds of the present invention were evaluatedby the above method. The results summarized in Table 4.

TABLE 4 PGI₂ receptor affinity Example No. Ki (μM) 21 0.43 34 0.52 360.23

INDUSTRIAL APPLICABILITY

The compounds of the present invention have the strong TXA₂ receptorantagonistic action and PGI₂ receptor agonistic action, and areeffective as medicines for treating or preventing diseases concerningTXA₂.

What is claimed is:
 1. A benzene fused heterocyclic derivative,represented by the following formula (II):

wherein A¹ is —O— or —S—; A² is

A³ is alkylene having 1 to 4 carbon atoms, alkenylene having 2 to 4carbon atoms, or alkynylene having 2 to 4 carbon atoms; A⁴ is—S(O)_(p)—, —O—, —CH₂—, —NR⁵—, —NR⁵CO—, or —CONR⁵—, wherein R⁵ ishydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may besubstituted by a group or groups selected from alkyl having 1 to 5carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms,phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylaminohaving 1 to 5 carbon atoms), and p is an integer of 0 to 2; m is 1; R¹is —X—(CH₂)_(n)—COOR⁶, wherein X is —O—, —S—, or —CH₂—, R⁶ is hydrogen,alkyl having 1 to 5 carbon atoms, or an atom or group which gives apharmacologically acceptable salt, and n is an integer of 1 to 3; R² isselected from the group consisting of: (1) phenyl and naphthyl, whereinphenyl or naphthyl may be substituted by a group or groups selected fromalkyl having 1 to 5 carbon atoms, phenyl hydroxyl, alkoxy having 1 to 5carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino,and alkylamino having 1 to 5 carbon atoms; or (2) alkyl having 1 to 5carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to5 carbon atoms, wherein alkyl, alkenyl, or alkynyl is substituted by oneor two Ar (wherein Ar is defined as the same as the above, and may befurther substituted by a group or groups selected from —OH, —CF₃, andcycloalkyl having 3 to 8 carbon atoms); R³ is hydrogen, halogen, alkylhaving 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; andeither or both of A¹ and A² contain a hetero atom other than carbon. 2.A benzene fused heterocyclic derivative according to claim 1, wherein R¹is —O—(CH₂)_(n)—COOR⁶.
 3. A benzene fused heterocyclic derivativeaccording to claim 1, wherein A³ is alkylene having 1 to 4 carbon atoms.4. A benzene fused heterocyclic derivative according to claim 3, whereinA⁴ is —S(O)_(p)— and p represents an integer of 0 to
 2. 5. Apharmaceutical composition comprising a therapeutically effective amountof a benzene fused heterocyclic derivative according to any one ofclaims 1, 2, 3, or 4 as an active ingredient and a pharmaceuticallyacceptable carrier.
 6. A thromboxane A₂ receptor antagonist comprising abenzene fused heterocyclic derivative according to any one of claims 1,2, 3 or 4 as an active ingredient.
 7. A thromboxane A₂ receptorantagonist having a PGI₂ receptor agonistic action, comprising a benzenefused heterocyclic derivative according to any of claims 1, 2, 3 or 4 asan active ingredient.
 8. A pharmaceutical composition for treatinghumans having hypertension, thrombosis, ischemic heart diseases,cerebral circulatory disorders, peripheral circulatory disorders,arteriosclerosis, platelet functional disorders, hyperlipidemia,nephritis, asthma, or allergic diseases, comprising a benzene fusedheterocyclic derivative according to any one of claims 1, 2, 3 or 4 asan active ingredient.
 9. A pharmaceutical composition for preventingdiseases in humans at high risk for developing one or more said disease,wherein said diseases comprise hypertension, thrombosis, ischemic heartdiseases, cerebral circulatory disorders, peripheral circulatorydisorders, arteriosclerosis, platelet functional disorders,hyperlipidemia, nephritis, asthma, or allergic diseases, said medicinecomprising a benzene-fused heterocyclic derivative according to any oneof claims 1, 2, 3 or 4 as an active ingredient.
 10. A pharmaceuticalcomposition according to claim 5, wherein said pharmaceuticallyacceptable carrier comprises one or more of starch, lactose, sucrose,crystalline cellulose, an excipient, a colorant, a lubricant, a binder,a disintegrant, and a coating agent.
 11. A pharmaceutical compositionaccording to claim 5, wherein said composition is in the form of asterilized solution.
 12. A pharmaceutical composition according to claim11, further comprising one or more of a tonicity agent, glucose, a pHregulator, and solution adjuvant.
 13. A pharmaceutical compositionaccording to claim 5, wherein the form of said composition is oneselected from the group consisting of tablets, powders, granules,solution, suppositories, ointments, or lotions.
 14. A method fortreating a disease related to high thromboxane A₂ activity in humanscomprising administering a therapeutically effective amount of abenzene-fused heterocyclic derivative according to any one of claims 1,2, 3 or
 4. 15. A method according to claim 14, wherein saidbenzene-fused heterocyclic.
 16. A method according to claim 15, whereinsaid benzene-fused heterocyclic derivative is administered 1 to 4 timesper day.
 17. A method according to claim 14, wherein said benzene-fusedheterocyclic derivative is administered by a method selected from thegroup consisting of intravenous injection, intraarterial injection,intramuscular injection, percutaneous administration, subcutaneousadministration, oral administration, or rectal administration.